Clinical Trials Register

Summary
EudraCT Number:	2021-003751-42
Sponsor's Protocol Code Number:	ICH-013-UroNEOadI
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:	2021-10-22
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

2021-003751-42

A.3

Full title of the trial

Randomized phase III clinical trial of Neo-Adjuvant Intravesical mitomycin C (MMC) treatment in patients with primary treatment-naïve vesical neoplasms.

Studio clinico randomizzato di fase III sull’efficacia del trattamento intravesicale con mitomicina C (MMC) in regime neo-adiuvante in pazienti con neoplasie vescicali naïve al trattamento primario.

A.3.1

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

n.a.

A.3.2

Name or abbreviated title of the trial where available

n.a.

A.4.1

Sponsor's protocol code number

ICH-013-UroNEOadI

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	IRCCS ISTITUTO CLINICO HUMANITAS
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	Medac Pharma S.r.l.
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	IRCCS Istituto Clinico Humanitas
B.5.2	Functional name of contact point	U.O. di Urologia
B.5.3	Address:
B.5.3.1	Street Address	Via A. Manzoni, 56
B.5.3.2	Town/ city	Rozzano (MI)
B.5.3.3	Post code	20089
B.5.3.4	Country	Italy
B.5.4	Telephone number	0282247744
B.5.6	E-mail	nadia.lo_iacono@cancercenter.humanitas.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.2.1.2	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	MITOMICINA
D.3.2	Product code	[n.a.]
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravesical use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MITOMICINA
D.3.9.2	Current sponsor code	n.a.
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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.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

Patients with primary treatment-naïve vesical neoplasms.

Pazienti con neoplasie vescicali naïve al trattamento primario.

E.1.1.1

Medical condition in easily understood language

Vesical neoplasms.

Neoplasie vescicali.

E.1.1.2

Therapeutic area

Diseases [C] - Male diseases of the urinary and reproductive systems [C12]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10046702
E.1.2	Term	Urogenital neoplasm
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

In this phase III clinical trial we will test the hypothesis that the neoadjuvant instillation of MMC in patients with vesical neoplasms induces the development of an antitumor response, which is effective in controlling tumor recurrence.

In questo studio clinico di fase III verificheremo l'ipotesi che l'instillazione neoadiuvante di MMC in pazienti con neoplasie vescicali induca lo sviluppo di una risposta antitumorale, efficace nel controllare la recidiva tumorale.

E.2.2

Secondary objectives of the trial

Secondary clinical endpoint:
1 Analysis of the rate of grade and stage progression in case of recurrence calculated after 3, 6, 12 and 24 months after TUR.
2 Correlation between clinical response and expression of the Mitomarker.

Secondary biological endpoints:
1. Analysis of the ability of MMC to induce ICD by measuring in midstream urine samples HMGB1, a known alarmin molecule, and interleukin (IL)-1ß, an inflammatory cytokine, that are known to be secreted by tumor cells undergoing ICD (13).
2. Analysis of specific changes in the urinary microbiome composition and correlation with ICD induction and clinical response, by performing microbiome profiling following a protocol established in the Rescigno laboratory.

Endpoint clinico secondario:
1. Analisi del tasso di progressione del grado e dello stadio istologico in caso di recidiva calcolato 3, 6, 12 e 24 mesi dopo TUR.
2. Correlazione tra risposta clinica ed espressione di Mitomarker.

Endpoint biologici secondari:
1. Analisi in campioni di urina di molecole note per essere secrete dalle cellule tumorali che vanno incontro a ICD.
2. Analisi della composizione del microbioma urinario e correlazione con l'induzione dell'ICD e con la risposta clinica.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Male and females, age >18 years old
- Primary “clinical” diagnosis of urinary bladder cancer and secondary recurrent untreated bladder cancer. The clinical diagnosis will be based on the combination of imaging (ultrasound, CT and MRI), flexible cystoscopy with NBI in out-patients regimen, and urine cytology assessment
- Urine cytology negative or positive
- Treatment naïve vesical neoplasm at time of enrollment
- Eastern Cooperative Oncology Group (ECOG) performance status < 2
- Multiple lesions with at least one lesion not smaller than 1 cm as diagnosed through cystoscopy
- Negative urinoculture at the beginning of neoadjuvant treatment
- Signed informed consent according to ICH/EU GCP, and national/local regulations. All patients have to provide written informed consent before study entry and all phases of this study will be in compliance with the Declaration of Helsinki.

- Uomini e donne, età> 18 anni
- Diagnosi primaria "clinica" del cancro della vescica urinaria e del carcinoma della vescica secondario ricorrente non trattato. La diagnosi clinica si baserà sulla combinazione di imaging (ecografia, TAC e risonanza magnetica), cistoscopia flessibile con NBI in regime ambulatoriale e valutazione della citologia urinaria
- Citologia urinaria negativa o positiva
- Tumore vescicale naïve al trattamento al momento dell'arruolamento
- Performance status dell'Eastern Cooperative Oncology Group (ECOG) < 2
- Lesioni multiple con almeno una lesione non inferiore a 1 cm diagnosticata mediante cistoscopia
- Urinocultura negativa all'inizio del trattamento
- Consenso informato firmato

E.4

Principal exclusion criteria

- Known hypersensitivity to MMC or any of its constituents
- Major surgery, other than diagnostic surgery
- Previous or concomitant cancer of the upper urinary tract or the prostatic urethra
- Previous (within the last 3 years) or current malignancies at other sites, except for adequately treated basal cell or squamous cell skin cancer or in situ carcinoma of the cervix uteri
- Presence of significant urologic disease (urethral stricture or hypospadias) interfering with intravesical therapy
- Pregnancy and breastfeeding status
- Current enrolment or participation in another therapeutic clinical trial within 4 weeks preceding treatment start
- Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator
- Treated with immunomodulatory agents (including cortisone treatment) at time of enrollment or in the two months before enrollment
- Treated with antibiotics at time of enrollment or during the month before enrollment
- Positive history of sexually transmitted diseases
- Suffering from an ongoing or recent (during the three months before enrollment) urinary infection
- Suffering from chronic intestinal inflammation

Due to the genotoxic potential of mitomycin, it is suggested to a man looking for offspring, during treatment and up to 6 months later to stock the sperm before the start of therapy due to the possibility of irreversible infertility caused by therapy.

- Nota ipersensibilità alla MMC
- Chirurgia maggiore
- Precedente o concomitante cancro del tratto urinario superiore o dell'uretra prostatica
- Tumori maligni negli ultimi 3 anni o attuali in altri siti
- Presenza di una significativa malattia urologica (stenosi uretrale o ipospadia) che interferisce con la terapia intravescicale
- Gravidanza o allattamento in corso
- Iscrizione in corso o partecipazione a un altro studio clinico terapeutico nelle 4 settimane precedenti l'inizio del trattamento
- Altre condizioni mediche o psichiatriche o psichiatriche acute o croniche gravi o anomalie di laboratorio che possono aumentare il rischio associato alla partecipazione allo studio o possono interferire con l'interpretazione dei risultati dello studio e renderebbero il paziente inappropriato per l'ingresso in questo studio o potrebbe compromettere gli obiettivi del protocollo secondo il parere dello sperimentatore
- Trattato con agenti immunomodulatori
- Trattati con antibiotici corrente o durante il mese precedente l'iscrizione
- Storia positiva di malattie a trasmissione sessuale
- Soffre di un'infezione urinaria in corso o recente
- Soffre di infiammazioni intestinali croniche

A causa del potenziale genotossico della mitomicina, si suggerisce ad un uomo in cerca di prole, durante il trattamento e fino a 6 mesi dopo di immagazzinare lo sperma prima dell'inizio della terapia a causa della possibilità di infertilità irreversibile causata dalla terapia.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study is to evaluate the efficacy of MMC neoadjuvant treatment in reducing the recurrence rate of vesical neoplasms. The success rate is measured as no recurrence and will be calculated as the proportion of patients who achieve a complete response following EAU guidelines (no evidence of cancer after 3, 6, 12 and 24 months after TUR).

L'endpoint primario dello studio è valutare l'efficacia del trattamento neoadiuvante di MMC nel ridurre il tasso di recidiva delle neoplasie vescicali. Il tasso di successo è misurato come assenza di recidiva e sarà calcolato come la percentuale di pazienti che ottengono una risposta completa seguendo le linee guida EAU (nessuna evidenza di cancro dopo 3, 6, 12 e 24 mesi dopo la TUR).

E.5.1.1

Timepoint(s) of evaluation of this end point

The selected time points are the ones in which according to the normal clinical practice control cystoscopies are schedules.

I time point selezionati sono quelli in cui secondo la normale pratica clinica sono programmate le cistoscopie di controllo.

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

The selected time points are the ones in which according to the normal clinical practice control cystoscopies are schedules.

I time point selezionati sono quelli in cui secondo la normale pratica clinica sono programmate le cistoscopie di controllo.

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

pazienti del gruppo controllo NON fanno trattamenti neoadiuvanti

control group patients do NOT do neoadjuvant treatments

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.8.6 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.1.1.1

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:

120

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

160

F.4.2

For a multinational trial

F.4.2.1

In the EEA

160

F.4.2.2

In the whole clinical trial

160

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)

n.a.

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

2021-10-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-01-25

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

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