Clinical Trials Register

Summary
EudraCT Number:	2017-001963-19
Sponsor's Protocol Code Number:	CaboPen
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-06-17
Trial results	View 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

2017-001963-19

A.3

Full title of the trial

Cabozantinib in patients with advanced penile squamous cell carcinoma (PSCC): an open-label, single-center, phase 2, single-arm trial (CaboPen)

Cabozantinib in pazienti affetti da neoplasia spinocellulare del pene avanzata (PSCC): studio monocentrico, a singolo braccio, in aperto, di fase 2 (CaboPen)

A.3.1

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

Cabozantinib in patients with advanced penile squamous cell carcinoma (PSCC): an open-label, single-center, phase 2, single-arm trial (CaboPen)

Cabozantinib in pazienti affetti da neoplasia spinocellulare del pene avanzata (PSCC): studio monocentrico, a singolo braccio, in aperto, di fase 2 (CaboPen)

A.3.2

Name or abbreviated title of the trial where available

CaboPen

A.4.1

Sponsor's protocol code number

CaboPen

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN00000000

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT00000000

A.5.3

WHO Universal Trial Reference Number (UTRN)

U0000-0000-0000

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	FONDAZIONE IRCCS "ISTITUTO NAZIONALE DEI TUMORI"
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	IPSEN S.p.A.
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	Fondazione IRCCS Istituto Nazionale dei Tumori
B.5.2	Functional name of contact point	Clinical Trial Center
B.5.3	Address:
B.5.3.1	Street Address	Via G. Venezian,1
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20133
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390223903067
B.5.5	Fax number	+390223903991
B.5.6	E-mail	trialcenter@istitutotumori.mi.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	CABOMETYX
D.2.1.1.2	Name of the Marketing Authorisation holder	Ipsen Pharma
D.2.1.2	Country which granted the Marketing Authorisation	France
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	CABOMETYX
D.3.2	Product code	[CABOMETYX]
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	Cabozantinib
D.3.9.1	CAS number	1140909-48-3
D.3.9.2	Current sponsor code	XL184, EXEL-7184, EXEL-02977184
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	60
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Cabozantinib
D.3.9.1	CAS number	1140909-48-3
D.3.9.2	Current sponsor code	XL184, EXEL-7184, EXEL- 02977184
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	40
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Cabozantinib
D.3.9.1	CAS number	1140909-48-3
D.3.9.2	Current sponsor code	XL184, EXEL-7184, EXEL- 02977184
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	20
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 advanced penile squamous cell carcinoma (PSCC)

Pazienti affetti da neoplasia spinocellulare del pene avanzata (PSCC).

E.1.1.1

Medical condition in easily understood language

Patients with advanced penile squamous cell carcinoma (PSCC).

Pazienti affetti da neoplasia spinocellulare del pene avanzata (PSCC)

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	10049570
E.1.2	Term	Penile neoplasm NOS
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the study will be to investigate the activity of daily oral doses of cabozantinib monotherapy until surgical removal of nodal disease (locally-advanced setting) or until disease progression or onset of unacceptable toxicity (metastatic setting).

L’obiettivo principale dello studio è quello di verificare l’attività antitumorale di cabozantinib in monoterapia fino a chirurgia (nel contesto localmente avanzato) o fino a progressione o comparsa di tossicità inaccettabile (nel contesto della malattia metastatica).

E.2.2

Secondary objectives of the trial

To evaluate the safety and tolerability of cabozantinib monotherapy in a population of advanced patients with PSCC.

Valutare la sicurezza e tollerabilità di cabozantinib in monoterapia nei pazienti affetti da neoplasia spinocellulare del pene.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Age 18-75
2) Written informed consent
3) ECOG performance status 0-1
4) Cytologically or histologically proven diagnosis of PSCC.
5) Histologically (Tru-cut biopsy) proven diagnosis of loco-regional nodal disease will be required in all cases except for those with clinical contraindications.
6) Uni- or bidimensionally measurable disease as defined by RECIST v1.1 criteria.
7) Clinical stage N2-3 and/or M1 (TNM 2002).
8) Locoregional relapse after prior major surgery/ies (either single or multiple).
9) No prior systemic therapy except for the administration of VBM chemotherapy (Vinblastine, Bleomycin, Methotrexate) for superficial disease if administered at least 6 months prior to study enrolment.
10) Adequate organ and marrow function.
11) Patients must be accessible for treatment and follow up as well as they must be willing and capable to comply with the requirements of the study. Patients registered on this trial must be treated and followed at the study sponsor site.

1) Età 18-75 anni
2) Consenso informato scritto
3) Performance status ECOG 0 o 1
4) Diagnosi citologica o istologica di PSCC.
5) La diagnosi istologica (mediante biopsia Tru-Cut) della malattia linfonodale sarà richiesta in tutti i casi, ad eccezione di quelli con controindicazioni cliniche.
6) Malattia misurabile come definito dai criteri RECIST v1.1
7) Stadio clinico N2-3 e o M1 (sec. TNM 2002)
8) Recidiva locoregionale dopo intervento di chirurgia maggiore (singolo o multiplo).
9)Nessuna precedente terapia sistemica ad eccezione della somministrazione di chemioterapia VBM (Vinblastina, Bleomicina, Metotrexato) per la malattia superficiale, se somministrata almeno 6 mesi prima dell'inizio dello studio
10)Adeguata funzione d’organo
11)I pazienti devono adeguati per ricevere il trattamento proposto. I pazienti che aderiscono a questo studio devono essere trattati e seguiti nel centro che propone lo studio.

E.4

Principal exclusion criteria

1) History of any one or more of the following cardiovascular conditions within the past 6 months:
- Cardiac angioplasty or stenting.
- Myocardial infarction.
- Unstable angina.
- Coronary artery by-pass graft surgery.
- Symptomatic peripheral vascular disease.
- Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA).
- Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted during the study but should be used with caution – please refer to the study drug
IB).
- Screening ECG with a QTc>450 msec, congenital long QT syndrome, history of sustained ventricular tachycardia, history of ventricular fibrillation or torsade de pointes,
bradycardia defined as heart rate < 50 bpm (patients with a pacemaker and heart rate > 50 bpm are eligible).
- Uncontrolled hypertension.
2) History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids or anti-seizure medication for 6 months ior to first dose of study drug.
3) History of HIV infection or active chronic hepatitis B or C.
4) Active clinically serious infections (> grade 2 NCI-CTC version 5.0).
5) Patients with seizure disorder requiring medication (such as steroids or anti-epileptics).
6) Patients undergoing renal dialysis
7) Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT treated basal cell carcinoma or any cancer curatively treated > 5 years prior to study entry.
8) History of clinically-significant gastrointestinal bleeding, inflammatory bowel disease, and other GI disorders associated with high risk of perforation or fistula formation or any other condition among those listed in the full protocol.
9) Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
10) Major surgery within 12 weeks before the first dose of study treatment. Note: Local surgery of isolated lesions for palliative intent is acceptable. Complete wound healing from major surgery must have occurred 1 month before inclusion and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before inclusion. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
11)History of allogenic organ solid transplantation.
12) Fertile males not willing to use a highly effective method of contraception or whose female partner is not using a highly effective contraception protection.
13) Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.
14) Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study.
15) Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drug.
16) Hemoptysis >=2.5 ml red blood within 3 months before treatment, signs indicative of pulmonary hemorrhage, cavitating pulmonary lesion, tumor invading major blood vessels and/or GI tract, endotracheal or endobronchial tumors History of clinically-significant gastrointestinal bleeding, inflammatory bowel disease, or any other condition among those listed in the full protocol.
17) Patients unable to swallow oral medications
18) Concomitant anticoagulation with oral anticoagulants or platelet inhibitors.
19) History of cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

1)Storia di una o più delle seguenti condizioni cardiovascolari negli ultimi 6 mesi:
- angioplastica cardiaca o stenting.
- infarto miocardico
- Angina instabile.
- Intervento chirurgico con innesto di by-pass dell'arteria coronaria.
- vascolopatia periferica sintomatica.
- insufficienza cardiaca congestizia di classe III o IV, come definito dalla New York Heart Association (NYHA).
- Aritmie cardiache che richiedono una terapia antiaritmica (i beta-bloccanti o la digossina sono consentiti durante lo studio ma devono essere usati con cautela ).
- ECG di screening con QTc> 450 msec, sindrome congenita del QT lungo, storia di tachicardia ventricolare sostenuta, storia di fibrillazione ventricolare o torsione
di punta, bradicardia definita come frequenza cardiaca <50 bpm (pazienti con pacemaker e frequenza cardiaca> 50 bpm sono ammissibili).
- Ipertensione non controllata
2) Anamnesi o evidenza clinica di metastasi al SNC o carcinomatosi leptomeningea, ad eccezione di soggetti che hanno metastasi al SNC precedentemente trattate, sono asintomatici e non hanno richiesto alcun trattamento con steroidi o antiepilettici per 6 mesi prima della prima dose del farmaco in studio.
3) Storia dell'infezione da HIV o epatite cronica attiva B o C.
4)Infezioni gravi attive
5) Pazienti con storia di epilessia che richiedono farmaci (come steroidi o antiepilettici).
6) Pazienti sottoposti a dialisi renale.
7) Storia di tumore precedente o concomitante ad eccezione di tumori superficiali radicalmente trattati (es. carcinoma basocellulare trattato) > 5 anni prima dell'ingresso nello studio.
8) Anamnesi di sanguinamento gastrointestinale significativo, malattia infiammatoria intestinale e altri disturbi gastrointestinali associati ad alto rischio di perforazione o formazione di fistole
9) Rari problemi ereditari di intolleranza al galattosio, il deficit di lattasi di Lapp o malassorbimento di glucosio-galattosio.
10) Chirurgia maggiore entro 12 settimane prima della prima dose del trattamento in studio. La guarigione completa della ferita da un intervento chirurgico maggiore deve essere avvenuta almeno 1 mese prima della prima dose del trattamento di studio. Interventi chirurgici minori (inclusi estrazioni dentali non complicate) entro 28 giorni prima della prima dose del trattamento di studio con guarigione completa della ferita almeno 10 giorni prima della prima dose del trattamento di studio. Soggetti con complicanze clinicamente rilevanti in atto e/o derivanti da un precedente intervento chirurgico non sono ammissibili.
11)Storia del trapianto allogenico di organi solidi.
12) uomini di età fertile che non accettano di utilizzare un metodo di contraccezione ad alta efficacia oppure le partner femminile che non utilizzano una protezione contraccettiva ad alta efficacia.
13)Abuso di sostanze, condizioni mediche, psicologiche o sociali che possono interferire con la partecipazione del paziente allo studio o la valutazione dei risultati dello studio.
14) Qualsiasi condizione instabile o che possa mettere a repentaglio la sicurezza del paziente e la sua adesione allo studio.
15) Reazione di ipersensibilità immediata nota o ritardata o idiosincrasia a farmaci chimicamente correlati al farmaco in studio.
16) Emottisi > = 2,5 ml di sangue rosso entro 3 mesi prima del trattamento, segni indicativi di emorragia polmonare, lesione cavitata polmonare, tumore che infiltra i vasi sanguigni maggiori e/o il tratto gastrointestinale, tumori endotracheali o endobronchiali. Storia di emorragia gastrointestinale clinicamente significativa, malattia infiammatoria intestinale o qualsiasi altra condizione tra quelle elencate nel protocollo completo.
17) Pazienti incapaci di deglutire i farmaci orali.
18) terapia con anticoagulanti concomitante (anticoagulanti orali) o inibitori piastrinici.
19) Storia di un evento cerebrovascolare, embolia polmonare o trombosi venosa profonda non trattata (TVP) negli ultimi 6 mesi.

E.5 End points

E.5.1

Primary end point(s)

Assessment of response-rate by RECIST v1.1 criteria. RR (%) = CR + PR, locally assessed by the investigator

Valutazione del tasso di risposta secondo i criteri RECIST v1.1. RR (%) = tasso confermato CR (risposte complete) + PR (risposte parziali), valutato localmente dallo sperimentatore.

E.5.1.1

Timepoint(s) of evaluation of this end point

Duration of the study

Durata dello Studio

E.5.2

Secondary end point(s)

• Assessment of the safety and tolerability: incidence, nature and severity of treatment-related adverse events will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0.; Pathologic complete response (pCR) rate as assessed in locally advanced patients undergoing surgery; Progression-free survival (PFS).; Overall Survival (OS).; Variations of the Quality of Life score as assessed with the Edmonton Symptom Assessment Scale (ESAS), validated in Italian language.; Analysis of circulating biomarkers; Correlative endpoints

Valutazione della sicurezza e della tollerabilità: l'incidenza, la natura e la gravità degli eventi avversi correlati al trattamento verranno classificate in base ai Common Terminology Criteria for Adverse Events (CTCAE) versione 5.0.; Percentuale di risposta patologica completa (pCR) valutata in pazienti localmente avanzati sottoposti a intervento chirurgico; Sopravvivenza libera da progressione (PFS).; Sopravvivenza generale (OS); Variazioni del punteggio di qualità della vita come valutato con la scala di valutazione dei sintomi di Edmonton (ESAS), convalidato in lingua italiana.; Analisi dei biomarcatori circolanti.; Endopoints correlativi

E.5.2.1

Timepoint(s) of evaluation of this end point

Duration of the study; Duration of the study; Duration of the study; Duration of the study.; Duration of the study.; Duration of the study; duration of the study

Durata dello studio; Durata dello Studio; Durata dello studio; Durata dello studio.; Durata dello studio.; Durata dello studio; durata dello studio

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

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)

follow up

Follow up

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

2019-05-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-04-15

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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IMP with orphan designation in the indication
Orphan Designation Number:
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