Clinical Trials Register

Summary
EudraCT Number:	2020-002727-11
Sponsor's Protocol Code Number:	CRO-2020-043
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:	2022-01-17
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

2020-002727-11

A.3

Full title of the trial

Neoadjuvant Chemotherapy followed by Pre-operative Chemoradiation and Consolidation Chemotherapy before Surgery in High Risk Rectal Cancer: Multicentric Phase II Study.

Chemioterapia Neoadiuvante, Radiochemioterapia Preoperatoria e Chemioterapia di Consolidamento seguite da Chirurgia nel Carcinoma del Retto ad Alto Rischio: Studio di fase II, multicentrico.

A.3.1

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

Neoadjuvant Chemotherapy followed by Pre-operative Chemoradiation and Consolidation Chemotherapy before Surgery in High Risk Rectal Cancer: Multicentric Phase II Study.

Chemioterapia Neoadiuvante, Radiochemioterapia Preoperatoria e Chemioterapia di Consolidamento seguite da Chirurgia nel Carcinoma del Retto ad Alto Rischio: Studio di fase II, multicentrico.

A.3.2

Name or abbreviated title of the trial where available

BRIDGE-2 Trial

A.4.1

Sponsor's protocol code number

CRO-2020-043

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	CENTRO DI RIFERIMENTO ONCOLOGICO
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	Sistema Sanitario Nazionale
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	Centro di riferimento oncologico
B.5.2	Functional name of contact point	Ufficio Clinical Trial
B.5.3	Address:
B.5.3.1	Street Address	via Franco Gallini 2
B.5.3.2	Town/ city	Aviano
B.5.3.3	Post code	33081
B.5.3.4	Country	Italy
B.5.4	Telephone number	0434659066
B.5.5	Fax number	0434659453
B.5.6	E-mail	gtabaro@cro.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	Oxaliplatino
D.3.2	Product code	[038107037]
D.3.4	Pharmaceutical form	Concentrate for solution for injection
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	Oxaliplatino
D.3.9.1	CAS number	63121-00-6
D.3.9.2	Current sponsor code	Oxaliplatino
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	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	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	Yes
D.2.1.1.1	Trade name	Capecitabina 150
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	Capecitabina 150 mg
D.3.2	Product code	[042501357]
D.3.4	Pharmaceutical form	Modified-release 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	Capecitabina
D.3.9.1	CAS number	154361-50-9
D.3.9.2	Current sponsor code	Capecitabina
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	150
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: 3
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
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	Capecitabina
D.3.2	Product code	[042501357]
D.3.4	Pharmaceutical form	Modified-release 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	Capecitabina
D.3.9.1	CAS number	154361-50-9
D.3.9.2	Current sponsor code	Capecitabina
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	500
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 locally advanced, potentially resectable, Middle-Distal Rectal Carcinoma, stage T3c-d N1-2, MRF + or T4N0-2, EMVI - / + (High-Risk)

Pazienti con Carcinoma del Retto Medio-Distale localmente avanzato, potenzialmente resecabile, stadio T3c-d N1-2, MRF+ o T4N0-2, EMVI-/+ (Alto-Rischio)

E.1.1.1

Medical condition in easily understood language

Patients with locally advanced, potentially resectable, Middle-Distal Rectal Carcinoma

Pazienti con Carcinoma del Retto Medio-Distale localmente avanzato, potenzialmente resecabile

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	LLT
E.1.2	Classification code	10007464
E.1.2	Term	Carcinoma rectum
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10038052
E.1.2	Term	Rectal carcinoma
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10007446
E.1.2	Term	Carcinoma of rectum
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

Determine the rate of Complete Pathological Remissions (pCR) after Chemotherapy Induction, Radiochemotherapy and Chemotherapy Consolidation in patients with High Risk Rectum Carcinoma.

Determinare il tasso di Remissioni Patologiche Complete (pCR) dopo Chemioterapia di induzione, Radiochemioterapia e Chemioterapia di Consolidamento nei pazienti con Carcinoma del Retto, Alto Rischio.

E.2.2

Secondary objectives of the trial

- Evaluate the feasibility of the therapeutic program (defined as the percentage of patients able to complete the entire therapeutic program compared to the number of patients enrolled in the study)
- Evaluate the rate of Resectability R0
- Evaluate complete and partial clinical remission (ycCR1 and ycPR1) to induction chemotherapy
- Evaluate the ycCR2 and ycPR2 after radiochemotherapy and chemotherapy consolidation
- Evaluate "Tumor Downstaging", defined as a comparison between clinical staging before and pathological staging after preoperative treatment
- Assess the toxicity and safety profile of each therapeutic phase
- Assess the morbidity and mortality (Clavien-Dindo) of the surgery postponed to end of the therapeutic program
- Evaluate Local Control, DFS and OS at 2-5 years.
- Assess the impact of treatment on patients' Quality of Life

- Valutare la Fattibilità del programma terapeutico (definita come percentuale di pazienti in grado di completare l’intero programma terapeutico rispetto al numero di pazienti arruolati in studio)
- Valutare il tasso di Resecabilità R0
- Valutare la remissione clinica completa e parziale (ycCR1 e ycPR1) alla Chemioterapia di induzione
- Valutare la ycCR2 e ycPR2 dopo Radiochemioterapia e Chemioterapia di consolidamento
- Valutare il “Tumor Downstaging”, definito come confronto fra la stadiazione clinica prima e quella patologica dopo il trattamento preoperatorio
- Valutare il profilo di Tossicità e Sicurezza di ogni fase terapeutica
- Valutare la Morbilità e Mortalità (Clavien-Dindo) dell’intervento chirurgico posposto al
termine del programma terapeutico
- Valutare il Controllo Locale, DFS e OS a 2-5 anni.
- Valutare l’impatto del trattamento sulla Qualità di Vita dei pazienti

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Adenocarcinoma of the middle distal rectum (up to 12 cm from the anal margin) documented histologically, stage T3c-dN1-2M0, MRF +, T4N0-2M0 (potentially operable), EMVI - / +
2. Age> 18
3. ECOG PS 0-1
4. Measurable disease according to RECIST 1.1
5. Able to understand the risks and benefits of the study
6. Neutrophils >/= 1.5 x 103/µL; Platelets >/= 100 x 103/µL; Bilirubin Tot </= 1.5 (UNL); ALT and AST </= 2.5 UNL, Alkaline Phosphatase </= 2.5 UNL; Creatinine clearance >50 ml/min or Creatinine </=1.5 UNL; Proteinuria
(stick) <2+ (if >/= 2+, perform 24-hour urine collection and verify that the value is </=1 g/24 hr).
7. Absence of mutational state with complete deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD); the presence of mutations associated with partial DPD deficit does not exclude eligibility (expected dose reduction of Fluoropyrimidine; see 7.1)
8. Absence of Grade> 1 neuropathy related to concomitant pathologies.
9. Absence of other malignancies within the last 5 years, except skin cancer and in situ carcinoma of the uterine cervix.
10. Absence of clinically significant heart disease.
11. No pregnancy or breastfeeding in progress.
12. Written informed consent

1. Adenocarcinoma del retto medio-distale (fino a 12 cm dal margine anale) documentato istologicamente, stadio T3c-dN1-2M0, MRF+, T4N0-2M0 (potenzialmente operabile), EMVI-/+
2. Età > 18
3. ECOG PS 0-1
4. Malattia misurabile secondo RECIST 1.1
5. In grado di comprendere rischi e vantaggi dello studio
6. Neutrofili >/= 1.5 x 103/µL; Piastrine >/= 100 x 103/µL; Bilirubina Tot </= 1.5 (UNL); ALT e AST </= 2.5 UNL, Fofatasi Alcalina </= 2.5 UNL; Creatinina clearance >50 ml/min or Creatinina </=1.5 UNL; Proteinuria
(stick) <2+ (se >/= 2+, eseguire raccolta urine 24-ore e verificare che il valore sia </=1 g/24 hr).
7. Assenza di stato mutazionale con deficit completo dell’enzima diidropirimidina deidrogenasi (DPD); la presenza di mutazioni associate a deficit parziale DPD non esclude l’eleggibilità (prevista riduzione di dose della Fluoropirimidina; vedi 7.1)
8. Assenza di neuropatia di Grado>1 correlata a patologie concomitanti.
9. Assenza di altre neoplasie entro gli ultimi 5 anni, eccetto il carcinoma della cute e il carcinoma in situ della cervice uterina.
10. Assenza di cardiopatia clinicamente significativa.
11. Assenza di gravidanza o allattamento in corso.
12. Consenso informato scritto

E.4

Principal exclusion criteria

1. Previous radiotherapy on the pelvis.
2. Clinically significant (active) cardiovascular disease, e.g. cerebrovascular events (</=6 months), myocardial infarction (</=6 months), unstable angina, congestive decompensation grade II or greater according to New York Heart Association (NYHA), cardiac arrhythmia in therapy.
3. Presence of genotypes with complete DPD enzyme deficiency.
4. Gastrointestinal affections with malabsorption syndrome, impossibility of taking oral medications.

1. Precedente radioterapia sulla pelvi.
2. Malattia cardiovascolare clinicamente significativa (attiva), es. fatti cerebrovascolari (</=6 mesi), infarto miocardico (</=6 mesi), angina instabile, scompenso congestizio di grado II o maggiore secondo New York Heart Association (NYHA), aritmia cardiaca in terapia.
3. Presenza di genotipi con deficit completo dell’enzima DPD.
4. Affezioni gastrointestinali con sindrome di malassorbimento, impossibilità di assumere farmaci per via orale.

E.5 End points

E.5.1

Primary end point(s)

Define the rate of complete pathological remissions (pCR)

Definire il tasso di remissioni patologiche complete (pCR)

E.5.1.1

Timepoint(s) of evaluation of this end point

31 July 2028

31 Luglio 2028

E.5.2

Secondary end point(s)

cRRs, RoRate, Fattibilità, OS-DFS

E.5.2.1

Timepoint(s) of evaluation of this end point

31 July 2028

31 Luglio 2028

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)

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)

Case discussion based on patient's clinical conditions.

Discussione del caso in base alle condizioni cliniche della paziente.

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

2022-03-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-08-02

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

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