Clinical Trials Register

Summary
EudraCT Number:	2021-006501-30
Sponsor's Protocol Code Number:	MINOTAURO
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2022-11-17
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

2021-006501-30

A.3

Full title of the trial

PembrolizuMab beyond RECIST progression and oral metroNOmic cyclophosphamide in meTAstatic UROthelial cancer: a single-arm, multicentre, phase 2 trial: minotaURO study

PembrolizuMab oltre la progressIone RECIST e ciclofosfamide orale a dosaggio metroNOmico in pazienTi affetti da cArcinoma UROteliale metastatico: studio multicentrico, a braccio singolo di fase 2: studio minotaURO

A.3.1

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

Addiction of oral metronomic cyclophosphamide to Pembrolizumab in patients with metastatic urothelial carcinoma beyond the First progression who demonstrated clinical benefit

Aggiunta del trattamento metronomico (bassi dosi di chemioterapico con somministrazione continuativa) con ciclofosfamide orale all’immunoterapico corrente (pembrolizumab), in pazienti affetti da carcinoma uroteliale metastatico con primo riscontro di progressione ma con evidenza di beneficio clinico

A.3.2

Name or abbreviated title of the trial where available

MINOTAURO

A.4.1

Sponsor's protocol code number

MINOTAURO

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	ISTITUTI FISIOTERAPICI OSPITALIERI
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	REGINA ELENA NATIONAL CANCER INSTITUTE
B.5.2	Functional name of contact point	UOC ONCOLOGIA MEDICA 1
B.5.3	Address:
B.5.3.1	Street Address	VIA ELIO CHIANESI 53
B.5.3.2	Town/ city	ROMA
B.5.3.3	Post code	00144
B.5.3.4	Country	Italy
B.5.4	Telephone number	0652666919
B.5.6	E-mail	segreteriaom1@ifo.gov.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	ENDOXAN BAXTER - 50 MG COMPRESSE RIVESTITE 50 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	BAXTER S.P.A.
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	CICLOFOSFAMIDE
D.3.2	Product code	[2907]
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ciclofosfamide monoidrata
D.3.9.1	CAS number	50-18-0
D.3.9.2	Current sponsor code	L01AA01
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	50
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 metastatic urothelial carcinoma in treatment with pembrolizumab, as clinically indicated, beyond the First RECIST-defined progression who have a stable performance status and demonstrated clinical benefit without rapid disease progression

Pazienti affetti da carcinoma uroteliale metastatico in trattamento con immuno- checkpoint inibitori, con primo riscontro di progressione RECIST di malattia, performance status stabile ed evidenza di beneficio clinico

E.1.1.1

Medical condition in easily understood language

Patients with metastatic urothelial carcinoma in treatment with pembrolizumab beyond the First progression with stable performance status and demonstrated clinical benefit without disease progression

Pazienti affetti da carcinoma uroteliale metastatico in trattamento con Pembrolizumab, con primo riscontro di progressione di malattia, performance status stabile ed evidenza di beneficio clinico

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	10046722
E.1.2	Term	Urothelial carcinoma bladder stage IV
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

The primary end point is: non progressive rate at 6 months

Obiettivo principale dello studio è valutare il tasso di pazienti liberi da progressione di malattia (PFS) a 6 mesi

E.2.2

Secondary objectives of the trial

The secondary end points are: duration of response (DOR); disease control rate (DCR); time to progression (TTP); OS; safety. Exploratory Endpoints: To identify biomarkers in blood and tissue samples to evaluate the mechanism of immune-resistance Immunogenicity of pembrolizumab given in combination with metronomic cyclophoshamide

Obiettivi secondari sono: tasso di risposte obiettive (ORR: objective response rate; % CR+PR); durata della risposta (DOR:duration of response); tasso di controllo di malattia (DCR: disease control rate, definite CR+PR+SD); tempo alla progressione (TTP: time to progression)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age = 18 years;
• Histological diagnosis of urothelial carcinoma, Advanced or metastatic disease;
• PD-L1 expression: PD-L1 determined by immunohistochemistry (IHC; Dako 22C3 pharmDx assay; Agilent Technologies) at a local laboratory, with expressions scored using the combined positive score (CPS);
• Eastern Cooperative Oncology Group performance status (ECOG PS) =2;
• Adequate hematologic, renal, and hepatic function; RECIST 1.1 measurable disease;
• Ongoing Pembrolizumab, as clinically indicated (progression after platinum-based chemotherapy);
• Progression disease according to RECIST criteria; Criteria for receiving ICIs beyond RECIST v1.1 progression are: clinical benefit assessed by investigator, stable performance status, tolerance of treatment and no need to deliver immediate intervention to prevent serious complication of progression; iUPD(immune unconfirmed progressive disease according to iRECIST criteria); which require radiological confirmation; Oligometastatic disease: minimal metastatic state in which patients have a low burden of metastatic disease with only a small number of metastatic sites at initial presentation of their illness; Written informed consent

• Età = 18 anni; Diagnosi istologica di carcinoma uroteliale;
• Evidenza di malattia in fase avanzata o metastatica;
• Eastern Cooperative Oncology Group performance status (ECOG PS) =2;
• Adeguata funzionalità ematologica, renale ed epatica ;
• Lesioni misurabili secondo criteri RECIST 1.1;
• Trattamento ongoing con pembrolizumab, secondo le indicazioni prescrittive vigenti (dopo una precendente linea di chemioterapia a base di platino);
• Prima evidenza di progression di malattia secondi criteri RECIST; Criteri per continuare a ricevere ICI oltre la progressione RECIST v1.1: evidenza di beneficio clinico, performance status stabile, buona tolleranza al trattamento; evidenza di iUPD(immune unconfirmed progressive disease, definite secondo iRECIST criteria) che richieda conferma radiologica; Consenso informato scritto

E.4

Principal exclusion criteria

• Condition requiring treatment with glucocorticoids (equivalent to >10 mg of prednisone daily);
• Hyperprogression condiction definited as two-fold or greater increase in the tumor growth rate in terms of volume during immunotherapy or a time to treatment failure of less than 2 months or a greater than 50% increase in tumor burden in two diameters according to irRC compared with pre-immunotherapy imaging that was obtained within 2 months of the initiation of the immuno-oncology agent, or a greater than two fold increase in progression pace with one diameter or a two fold or greater increase in the tumor growth rate in one diameter on immunotherapy

• Condizioni cliniche che richiedano l’uso di corticosteroidi ad un dosaggio >10 mg di prednisone al giorno);
• Condizione di “Hyperprogression” definite come incremento del volume tumorale (= 2 volte il volume iniziale) durante l’immunoterapia o evidenza di progressione a meno di 2 mesi dall’inizio del trattamento immunoterapico con incremento >50% in 2 diametri sec criteri irRC

E.5 End points

E.5.1

Primary end point(s)

Non progressive rate at 6 months

Tasso di pazienti liberi da progressione di malattia (PFS) a 6 mesi

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

6 mesi

E.5.2

Secondary end point(s)

Overall Response Rate

tasso di risposte obiettive

E.5.2.1

Timepoint(s) of evaluation of this end point

3 months

3 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

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)

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

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

F.3.3.1

Women of childbearing potential not using contraception

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

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)

According to standard routine

Secondo 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

2023-11-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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