Clinical Trials Register

Summary
EudraCT Number:	2019-004782-40
Sponsor's Protocol Code Number:	PEM-PRO
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:	2021-01-21
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

2019-004782-40

A.3

Full title of the trial

An open label, single-arm, phase 2 study of neoadjuvant PEMbrolizumab before radical PROstatectomy (PEM-PRO) in high-risk prostate cancer patients

Studio di fase 2, open-lable, a braccio singolo sull’uso in neoadiuvante di pembrolizumab prima della prostatectomia radicale nei pazienti con tumore della prostata ad alto rischio (PEM-PRO)

A.3.1

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

A study of neoadjuvant PEMbrolizumab before radical PROstatectomy (PEM-PRO) in patients affected by high-risk prostate cancer

Studio di fase 2 a braccio singolo sull’uso della terapia neoadiuvante con pembrolizumab prima della prostatectomia radicale nei pazienti affetti da tumore della prostata ad alto rischio (PEM-PRO)

A.3.2

Name or abbreviated title of the trial where available

PEM-PRO

A.4.1

Sponsor's protocol code number

PEM-PRO

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	OSPEDALE SAN RAFFAELE
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	MERCK SHARP & DOHME CORP
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IRCCS Ospedale San Raffaele
B.5.2	Functional name of contact point	Unità Operativa di Urologia
B.5.3	Address:
B.5.3.1	Street Address	Via Olgettina 58
B.5.3.2	Town/ city	Milan
B.5.3.3	Post code	20132
B.5.3.4	Country	Italy
B.5.6	E-mail	gandaglia.giorgio@hsr.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	KEYTRUDA (pembrolizumab, MK 3475)
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme B.V. EU/1/15/1024/002
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	KEYTRUDA (pembrolizumab, MK 3475)
D.3.2	Product code	[MK 3475]
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	Pembrolizumab
D.3.9.1	CAS number	1374853-91-4
D.3.9.2	Current sponsor code	MK-3475
D.3.9.4	EV Substance Code	SUB167136
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	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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	Pembrolizumab
D.3.2	Product code	[MK-3475]
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	Pembrolizumab
D.3.9.1	CAS number	1374853-91-4
D.3.9.2	Current sponsor code	MK-3475
D.3.9.4	EV Substance Code	SUB167136
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	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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	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	68GA-PSMA-HBED-CC
D.3.2	Product code	[68GA-PSMA-HBED-CC]
D.3.4	Pharmaceutical form	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	PSMA-HBED-CC (PSMA-11)
D.3.9.2	Current sponsor code	68Ga-PSMA
D.3.9.3	Other descriptive name	68Ga-PSMA
D.3.10	Strength
D.3.10.1	Concentration unit	MBq megabecquerel(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	110 to 210
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

High-risk prostate cancer

Tumore della prostata ad alto rischio

E.1.1.1

Medical condition in easily understood language

Prostate cancer at high risk of biochemical recurrence after surgery

Tumore della prostata considerato ad alto rischio di recidiva biochimica

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	10026389
E.1.2	Term	Malignant neoplasm of prostate
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

To assess if neoadjuvant therapy with pembrolizumab is associated with pathologic changes at radical prostatectomy and with a reduction in the rate of lymph node invasion in prostate cancer patients at high risk of recurrence after surgery.

Valutare se la somministrazione di pembrolizumab in neoadiuvante induce una risposta patologica e riduce il rischio di invasione linfonodale nei pazienti con tumore della prostata ad alto rischio candidati a intervento chirurgico

E.2.2

Secondary objectives of the trial

- To evaluate radiological response in terms of reduction of tumour volume at preoperative mpMRI on those patients with measurable disease at baseline. Radiological response will be defined as a tumour reduction of 30% in the maximum diameter of the index lesion as measured by mpMRI
- To test the impact of neoadjuvant pembrolizumab on the risk positive surgical margins at final pathology
- To test the impact of neoadjuvant pembrolizumab on the risk of PSA persistence after surgery
- To assess the safety and side effects of pembrolizumab in PCa patients undergoing surgery

- Valutare la risposta radiologica al trattamento con pembrolizumab definita come una riduzione del 30% del volume tumorale alla mpMRI
- Valutare se la somministrazione di pembrolizumab riduce il rischio di margini chirurgici positivi
- Valutare se la somministrazione di pembrolizumab riduce il rischio di persistenza di elevati valori di PSA dopo chirurgia
- Determinare la sicurezza e gli effetti collaterali della somministrazione di pembrolizumab nei pazienti con tumore della prostata

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of prostate cancer
2. PCa detected at prostate biopsy with a risk of lymph node invasion higher than 5% according to the Briganti nomogram
3. The participant should be fit and planned for RP and ePLND
4. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
5. Did not start novel therapies within the 4 weeks before the beginning of the study

1. Pazienti di sesso maschile, di età fra i 18 e gli 80 anni.
2. Biopsia prostatica per tumore della prostata, con rischio di invasione linfonodale maggiore di 5% secondo il nomogramma di Briganti.
3. Eleggibilità alla prostatectomia radicale robot-assistita con linfoadenectomia pelvica estesa.
4. Paziente in grado di intendere e di volere, volontà di firmare il consenso informato.
5. Se in terapia cronica, dosi stabili da almeno 4 settimane prima dell’ingresso nello studio.

E.4

Principal exclusion criteria

1. Has received prior systemic anti-cancer therapy including investigational agents prior to allocation.
2. Unable to complete the diagnostic investigations required per protocol
3. Evidence of metastases at preoperative imaging
4. Evidence of lymph node invasion before surgery
5. Life expectancy shorter than 12 months
6. History of chemotherapy
7. History of brachytherapy or EBRT
8. Cardiovascular diseases not controlled by medical therapy
9. Hearth failure
10. Clinically relevant hepatic or renal diseases
11. Onset of cerebral diseases within 6 months before the study beginning
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator

1. Somministrazione di altre terapie neoadiuvanti.
2. Impossibilità a completare le indagini diagnostico/strumentali richieste dal protocollo.
3. Malattia metastatica alla diagnosi.
4. Evidenza di invasione linfonodale alla diagnosi.
5. Aspettativa di vita inferiore a 12 mesi.
6. Pregressa chemioterapia.
7. Pregressa brachiterapia o radioterapia a fasci esterni.
8. Malattie cardiovascolari non compensate.
9. Scompenso cardiaco congestizio.
10. Malattia epatobiliare o renale clinicamente significativa.
11. Storia di malattia cerebrale nei 6 mesi precedenti.
12. Qualsiasi altra malattia o disturbo che, all’opinione dell’investigatore, potrebbe o porre il paziente a rischio a causa dello studio, o influenzare il risultato dello studio, o, ancora, la capacità del paziente a partecipare allo studio.

E.5 End points

E.5.1

Primary end point(s)

A reduction of 50% in the rate of node positive patients compared to what currently reported in the literature represents the main endpoint of the study (rate of pN0 of 85 vs. 70%)

La riduzione del rischio di invasione linfonodale è definita come una riduzione del 50% dei pazienti con linfonodi positivi rispetto a quanto riportato attualmente in letteratura nella stessa popolazione (85% di pazienti liberi da malattia linfonodale rispetto al 70% attualmente riportato in letteratura per la stessa popolazione di pazienti).

E.5.1.1

Timepoint(s) of evaluation of this end point

Pathologic assessment of surgical specimens (within 4 weeks after surgery)

Analisi istologica della prostatectomia (entro 4 settimane da intervento)

E.5.2

Secondary end point(s)

Positive margins, PSA persistence after surgery,

Margini chirurgici positivi, persistenza di PSA dopo l’intervento, riduzione radiologica del volume tumorale, complicanze ed effetti collaterali

E.5.2.1

Timepoint(s) of evaluation of this end point

Up to 2 years after radical prostatectomy

Sino a 2 anni dopo intervento chirurgico

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

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:

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

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)

The follow-up will be planned according to clinical international guidelines and will be based on the evaluation of serum PSA levels, imaging in the case of biochemical recurrence and periodic follow-up visits.

I pazienti verranno seguiti con il follow-up previsto dalle linee guida internazionali per il tumore della prostata basato sul dosaggio dei valori di PSA nel tempo, imaging nel caso di recidiva e visite periodiche.

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

2020-09-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-07-15

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

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