Clinical Trials Register

Summary
EudraCT Number:	2022-001939-88
Sponsor's Protocol Code Number:	IRST157.04
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:	2022-11-28
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

2022-001939-88

A.3

Full title of the trial

Phase II study of Gemcitabine plus Nab-Paclitaxel in combination with Losartan followed by Stereotactic Radiotherapy for Locally Advanced Pancreatic Cancer

Studio di Fase II di Gemcitabina e Nab-Paclitaxel in associazione a Losartan seguiti da Radioterapia Stereotassica per Tumore del Pancreas Localmente Avanzato

A.3.1

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

Clinical study on the combination of Losartan (antihypertensive drug) and chemotherapy followed by stereotactic radiotherapy, a non-invasive radiotherapy technique, for the treatment of locally advanced pancreatic cancer

Studio clinico sulla combinazione di Losartan (farmaco antipertensivo) e chemioterapia seguito da radioterapia stereotassica, tecnica radioterapica non invasiva, per il trattamento del Tumore del Pancreas Localmente Avanzato

A.3.2

Name or abbreviated title of the trial where available

OVERPASS

A.4.1

Sponsor's protocol code number

IRST157.04

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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IRCCS IRST
B.5.2	Functional name of contact point	Centro di Coordinamento studi IRST
B.5.3	Address:
B.5.3.1	Street Address	Via P. Maroncelli 40
B.5.3.2	Town/ city	Meldola (FC)
B.5.3.3	Post code	47014
B.5.3.4	Country	Italy
B.5.4	Telephone number	0544287167
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	LOSARTAN DOC GENERICI - 12.5 MG COMPRESSE RIVESTITE CON FILM 21 COMPRESSE IN BLISTER PVC/PVDC/PELLICOLA DI ALLUMINIO
D.2.1.1.2	Name of the Marketing Authorisation holder	DOC GENERICI SRL
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	Losartan DOC 12,5 mg
D.3.2	Product code	[Losartan DOC 12, 5 mg]
D.3.4	Pharmaceutical form	Film-coated 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	LOSARTAN POTASSICO
D.3.9.1	CAS number	124750-99-8
D.3.9.2	Current sponsor code	LOSARTAN
D.3.9.4	EV Substance Code	SUB02974MIG
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	12.5
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	LORTAAN - 50 MG COMPRESSE RIVESTITE CON FILM 28 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	MSD ITALIA S.R.L.
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	LORTAAN
D.3.2	Product code	[LORTAAN]
D.3.4	Pharmaceutical form	Film-coated 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	LOSARTAN POTASSICO
D.3.9.1	CAS number	124750-99-8
D.3.9.2	Current sponsor code	LOSARTAN
D.3.9.4	EV Substance Code	SUB02974MIG
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

Unresectable locally advanced, non-metastatic pancreatic cancer (as described by NCCN guidelines version 1.2022)

Tumore del pancreas localmente avanzato non resecabile (come da linee guida NCCN versione 1.2022)

E.1.1.1

Medical condition in easily understood language

Locally advanced non-metastatic and non-operable pancreatic cancer

Tumore del pancreas localmente avanzato non metastatico e non operabile

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10065147
E.1.2	Term	Malignant solid tumor
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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	10052747
E.1.2	Term	Adenocarcinoma pancreas
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

Step A: To assess the safety of GEM-Nab-Paclitaxel and Losartan association followed by stereotactic radiation.
Step B: To assess the activity, in terms of resectability rate, of the study treatment.

Step A: Valutare la sicurezza dell'associazione GEM-Nab-Paclitaxel e Losartan seguita da radiazione stereotassica.
Step B: Valutare l'attività, in termini di tasso di resecabilità, del trattamento in studio.

E.2.2

Secondary objectives of the trial

Margin-negative resection rate (R0), progression-free survival (PFS), overall survival (OS) blood biomarkers response, and safety and quality of life..

Tasso di resezione con margine negativo (R0), la sopravvivenza libera da progressione (PFS), la sopravvivenza globale (OS), la risposta dei biomarcatori ematici, la sicurezza e la qualità della vita.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients with histologically or cytologically confirmed pancreatic carcinoma
2. Clinical stage I-III, according to TNM 8th ed.
3. Locally advanced disease, as defined per NCCN Guidelines version 1.2022 (Appendix D)
4. Baseline systolic blood pressure (SBP) = 100 mmHg
5. Age >18 years and =75 years.
6. Life expectancy greater than 12 weeks.
7. ECOG performance status 0-2 (see Appendix A).
8. Presence of at least one measurable lesion in agreement to RECIST 1.1 criteria
9. Patients must have normal organ and marrow function
10. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
11. Ability to understand and the willingness to sign a written informed consent document.

1. Pazienti con carcinoma pancreatico confermato istologicamente o citologicamente
2. Stadio clinico I-III, secondo il TNM 8a edizione.
3. Malattia localmente avanzata, secondo la definizione delle linee guida NCCN versione 1.2022
4. Pressione arteriosa sistolica (SBP) basale = 100 mmHg
5. Età >18 anni e =75 anni.
6. Aspettativa di vita superiore a 12 settimane.
7. ECOG performance status 0-2
8. Presenza di almeno una lesione misurabile secondo i criteri RECIST 1.1.
9. I pazienti devono avere una funzione d'organo e midollare normale.
10. Le donne in età fertile e gli uomini devono accettare di utilizzare una contraccezione adeguata (metodo ormonale o di barriera per il controllo delle nascite; astinenza) prima dell'ingresso nello studio e per tutta la durata della partecipazione allo studio. Se una donna rimane incinta o sospetta di esserlo durante la partecipazione a questo studio, deve informare immediatamente il proprio medico curante.
11. Capacità di comprendere e disponibilità a firmare il consenso informato.

E.4

Principal exclusion criteria

1. Clinical stage IV, according to TNM 8th ed.
2. Patients who have previously received chemotherapy or radiotherapy for pancreatic cancer.
3. Participation in another clinical trial with any investigational agents within 30 days prior to study screening.
4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to any agent used in the study.
5. Serious concomitant systemic disorders incompatible with the study (at discretion of the investigator);
6. Patient already treated on other Losartan dosages than those prescribed by protocol or treated on other Angiotensin II Receptor Blockers (ARB) therapy for hypertension or renal protection (with diabetes) at the time of enrolment;
7. Baseline hypotension, defined as systolic BP lower than 100 mmHg on two readings obtained on two separated days prior to study enrolment.
8. 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.

1. Stadio clinico IV, secondo il TNM 8a edizione.
2. Pazienti che hanno ricevuto in precedenza chemioterapia o radioterapia per il cancro al pancreas.
3. Partecipazione ad un altro studio clinico con farmaci sperimentali nei 30 giorni precedenti lo screening dello studio.
4. Storia di reazioni allergiche attribuite a composti di composizione chimica o biologica simile a qualsiasi farmaco utilizzato nello studio.
5. Gravi patologie sistemiche concomitanti incompatibili con lo studio (a discrezione dello sperimentatore);
6. Paziente già in trattamento con dosaggi di Losartan diversi da quelli prescritti dal protocollo o in terapia con altri bloccanti del recettore dell'angiotensina II (ARB) per l'ipertensione o la protezione renale (con diabete) al momento dell'arruolamento;
7. Ipotensione basale, definita come pressione sistolica inferiore a 100 mmHg in due letture ottenute in due giorni separati prima dell'arruolamento nello studio.
8. Malattie intercorrenti non controllate, tra cui, ma non solo, infezioni in corso o attive, insufficienza cardiaca congestizia sintomatica, angina pectoris instabile, aritmia cardiaca o malattie psichiatriche/situazioni sociali che limiterebbero la conformità ai requisiti dello studio.

E.5 End points

E.5.1

Primary end point(s)

- Step A: Number of participants discontinuing study treatment due to treatment related G=3 AEs. Toxicity assessments will be done using the NCI Common Terminology Criteria for Adverse Events (CTCAE v 5.0).
- Step B: Rate of patients undergoing surgery on total patient population. Resectability will be determined by Multidisciplinary team according.

- Fase A: numero di partecipanti che interrompono il trattamento dello studio a causa di AE G=3 correlati al trattamento. La valutazione della tossicità sarà effettuata utilizzando i criteri NCI Common Terminology Criteria for Adverse Events (CTCAE v 5.0).
- Fase B: Tasso di pazienti sottoposti a chirurgia sulla popolazione totale di pazienti. La resecabilità sarà determinata da un team multidisciplinare.

E.5.1.1

Timepoint(s) of evaluation of this end point

40 months

40 mesi

E.5.2

Secondary end point(s)

margin-negative resection rate (R0); blood biomarkers response; progression-free survival (PFS); overall survival (OS); safety; quality of life

tasso di resezione con margine negativo (R0); risposta dei biomarcatori del sangue; sopravvivenza libera da progressione (PFS); sopravvivenza globale (OS); sicurezza; qualità della vita

E.5.2.1

Timepoint(s) of evaluation of this end point

40 months; 80 months; 80 months; 80 months; 40 months; 40 months

40 mesi; 80 mesi; 80 mesi; 80 mesi; 40 mesi; 40 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

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

Yes

E.6.13.1

Other scope of the trial description

Resecability rate

Tasso di resecabilità

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 end of study is 6 months after last patient last visit or the date of death of the last patient whatever comes first.

La fine dello studio è prevista 6 mesi dopo l'ultima visita dell'ultimo paziente o la data di morte dell'ultimo paziente, a seconda di quale avvenga per prima.

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

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)

Patients will be followed every three months until disease progression or up to 36 months after end of treatment.

I pazienti saranno seguiti ogni tre mesi fino alla progressione della malattia o fino a 36 mesi dopo la fine del trattamento.

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

2022-12-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-02-17

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

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