Clinical Trials Register

Summary
EudraCT Number:	2017-003103-22
Sponsor's Protocol Code Number:	BONSAI
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:	2021-06-08
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

2017-003103-22

A.3

Full title of the trial

Advanced or Metastatic Collecting ducts renal cell carcinoma

Cabozantinib nel carcinoma renale dei dotti collettori di Bellini.

A.3.1

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

Advanced or Metastatic Collecting ducts renal cell carcinoma

Cabozantinib nel carcinoma renale dei dotti collettori di Bellini.

A.3.2

Name or abbreviated title of the trial where available

BONSAI

A.4.1

Sponsor's protocol code number

BONSAI

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.5.4

Other Identifiers

Name:

BONSAI

Number:

BONSAI

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	0223902190
B.5.5	Fax number	0223903991
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.3.4	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	20
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	60
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

Collecting Duct Renal Cell Carcinoma

Carcinoma renale dei dotti collettori di Bellini (CDC)

E.1.1.1

Medical condition in easily understood language

Collecting Duct Renal Cell Carcinoma

Carcinoma renale dei dotti collettori di Bellini (CDC)

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	10073252
E.1.2	Term	Carcinoma of the collecting ducts of Bellini
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

To evaluate activity of Cabozantinib in terms of ORR according to the RECIST 1.1 criteria.

Valutare l¿attivit¿ di cabozantinib in termini di ORR secondo i criteri RECIST 1.1

E.2.2

Secondary objectives of the trial

- To evaluate PFS and OS;
- To evaluate tolerability of Cabozantinib.

- Valutare la PFS e la OS;
- Valutare la tollerabilit¿ di cabozantinib.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Written Informed Consent Form
2.Unresectable, advanced or metastatic collecting ducts carcinoma untreated with any systemic agent for advanced disease
3.Measurable disease as defined by RECIST v1.1 criteria
4.Age =18 years
5.ECOG Performance Status 0-1
6.Any of the following laboratory test findings:
-Hemoglobin > 9 g/dL (5.6 mmol/L)
-WBC > 2,000/mm3
-Neutrophils > 1,500/mm3
-Platelets > 100,000/mm3
-AST or ALT < 3 x ULN (< 5 x ULN if liver metastases are present)
-Total Bilirubin < 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
-Serum creatinine < 1.5 x upper limit of normal (ULN) or creatinine clearance = 40 mL/min (measured or calculated by Cockroft-Gault formula)
-Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of pancreatitis
-PT-INR/PTT = 1.5 x upper limit of normal [Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists.] For patients on warfarin, close monitoring of at least weekly evaluations will be performed, until INR is stable based on a measurement at pre-dose, as defined by the local standard of care.
7.Availability of a representative FFPE tumor specimen collected within 24 months of starting first-line cabozantinib that enables the definitive diagnosis of CDC (the archival specimen must contain adequate viable tumor tissue to enable candidate biomarkers status; the specimen may consist of a tissue block or at least 15 unstained serial sections; for core needle biopsy specimens, at least two cores should be available for evaluation)
8.Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the study and for 4 months after the last dose of study treatment
9.Female subjects of childbearing potential must not be pregnant at screening.

1.Il consenso informato scritto deve essere ottenuto prima di ogni procedura relativa allo studio.
2.Pazienti con diagnosi istologica di carcinoma renale dei dotti collettori (CDC) non resecabile, in fase avanzata o metastatica
3. Malattia metastatica misurabile (secondo criteri RECIST v.1.1)
4. Età = 18 anni
5. ECOG Performance Status di 0 o 1
6. Adeguata funzionalità midollare epatica e renale come dimostrato dai
parametri ematici eseguiti alla visita di screening e che devono essere:
- Emoglobina = 9 g/dl (o 5.6 mmol/L)
- Conta dei neutrofili (ANC) >1,500/mm3
- Conta Piastrinica = 100,000/ mm3
- ALT e AST = 3 x il limite superiore di normalità (< 5 x il limite superiore di normalità se sono presenti metastasi epatiche)
- Bilirubina totale = 1.5 x il limite superiore di normalità (ad eccezione dei pazienti con Sindrome di Gilbert, che possono avere un valore di bilirubina totale < 3.0 mg/dL)
- Creatinina sierica < 1.5 x il limite superiore di normalità o clearance della creatinina = 40 mL/min (misurato o calcolato mediante la formula di Cockroft-Gault)
- Lipasi < 2.0 x il limite superiore di normalità e non evidenza radiologica o clinica di pancreatite
- PT-INR/PTT = 1.5 x il limite superiore di normalità [pazienti in corso di terapia eparinica o con coumadin possono partecipare allo studio se questi parametri non erano alterati prima dell’inizio della terapia anticoagulante]. Per i pazienti in trattamento con warfarin un monitoraggio settimanale dell’INR
è raccomandato fino a stabilizzazione dei valori.
7. Tessuto tumorale d’archivio raccolto entro 24 mesi dall’inizio di cabozantinib in prima linea che abbia consentito la diagnosi di CDC (l’archivio tumorale deve contenere adeguato tessuto tumorale per valutare lo status marcatoriale; il campione può essere costituito da un blocchetto in paraffina o almeno 15 sezioni in bianco; per campioni derivati da biopsie, sono necessari almeno due cores per l’analisi).
8. Le donne in età fertile ed i loro partner devono adottare adeguati sistemi di protezione (ad esempio profilattici o diaframmi con gel spermicida) durante il corso del trattamento e per almeno 4 mesi dopo l’interruzione del trattamento.
9. Le donne in età fertile non devono essere in gravidanza allo screening.

E.4

Principal exclusion criteria

1.Previous therapy for advanced disease; any medical adjuvant treatment must have been stopped at least six months before entry into the study
2.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 bypass graft surgery, symptomatic peripheral vascular disease, Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)
3.Poorly controlled hypertension [defined as systolic blood pressure (SBP) of =140 mmHg or diastolic blood pressure (DBP) of = 90mmHg].
4.History of cerebrovascular accidents, including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible
5.Major surgery or trauma within 28 days before to study entry; the presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major surgery).
6.Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before randomization.
7.Evidence of active bleeding or bleeding diathesis and/or clinically-significant GI bleeding within 6 months before the first dose of study treatment; 3 months for pulmonary hemorrhage and patients with tumor invading or encasing any major blood vessels.
8.Patients with GI disorders associated with a high risk of perforation or fistula formation.
9.Subjects with clinically relevant ongoing complications from prior radiation therapy.
10.Any serious and/or unstable pre-existing medical, psychiatric, or other conditions that could interfere with subject’s safety, provision of informed consent, or compliance to study procedures.
11.Previous or ongoing treatment (except for adjuvant therapies) with any of the following anti-cancer therapies: chemotherapy, immunotherapy, target therapies, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of Cabozantinib
12.Inability to swallow tablets or capsules.

1.Precedente terapia per malattia avanzata; qualunque trattamento adiuvante deve essere stato terminato almeno 6 mesi prima l’entrata nello studio.
2. Storia di una qualsiasi o più delle seguenti condizioni cardiovascolari negli ultimi 6 mesi: angioplastica coronarica o posizionamento di stent coronarici, infarto del miocardio, angina instabile, intervento chirurgico di bypass coronarico, malattia vascolare periferica sintomatica, insufficienza cardiaca congestizia, classe III o IV, come definito dal New York Heart Association (NYHA).
3. Ipertensione arteriosa scarsamente controllata [definita come pressione arteriosa sistolica (SBP) di = 140 mmHg o pressione diastolica (DBP) di = 90 mmHg]
4. Storia di eventi cerebrovascolari compresi: attacco ischemico transitorio (TIA), embolia polmonare o trombosi venosa profonda (TVP) non trattata negli ultimi 6 mesi. Nota: I soggetti con recente TVP che sono stati trattati con farmaci anti-coagulanti per almeno sei settimane sono eleggibili.
5. Chirurgia maggiore o trauma entro 28 giorni dalla prima dose di farmaco e/o presenza di qualsiasi ferita, frattura, o ulcera non guarita (procedure, come il posizionamento del catetere non considerati interventi di chirurgia maggiore).
6. Metastasi al basale del sistema nervoso centrale (CNS), con l'eccezione dei soggetti precedentemente trattati per metastasi del SNC (chirurgia ± radioterapia, radiochirurgia, o gamma-knife), e che siano stabili da almeno 3 mesi.
7. Evidenza di sanguinamento attivo o diatesi emorragica gastrointestinale entro i 6 mesi precedenti l’inizio della terapia (3 mesi per sanguinamenti polmonari o lesioni infiltranti i grandi vasi polmonari che aumentano il rischio di emorragia polmonare endobronchiale.
8. Pazienti con disordini gastrointestinali associati ad un alto rischio di perforazione o fistolizzazione.
9. Soggetti con complicazioni di rilievo in atto derivanti da un precedente trattamento radioterapico.
10. Qualsiasi grave e/o instabile condizione medica, psichiatrica, o altra condizione preesistente che potrebbe interferire con la sicurezza del soggetto, la fornitura di consenso informato, o la compliance allo studio.
11. Trattamento con una qualsiasi delle seguenti terapie oncologiche: radioterapia, chirurgia o chemioembolizzazione entro i 14 giorni precedenti la prima dose di cabozantinib.
12. Incapacità a deglutire compresse o capsule.

E.5 End points

E.5.1

Primary end point(s)

Objective response rate (ORR)

Tasso di Risposta Obiettiva (ORR)

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)

Progression free survival (PFS); Overall survival (OS); Tolerability of cabozantinib; Exploratory objectives of this study:
¿to identify the somatic mutation profiles in CDC on disease associated targets by NGS;
¿to identify transcript fusions of selected genes by performing a RNA sequencing;
¿to monitor the immunological properties of tumor cells and the state of circulating immune cells, to assess the modulating activity of cabozantinib on local and systemic tumor immunity.

Sopravvivenza libera da progressione ( PFS); Sopravvivenza globale (OS); Tollerabilit¿ del farmaco Cabozantinib; Obiettivi esploratori dello studio:
-identificare un profilo di mutazioni somatiche nel CDC da effettuare sul tumore e su tessuto sano di controllo al basale tramite Next Generation Sequencing
-identificare gli RNA trascritti di geni selezionati mediante RNA sequencing;
-monitorare il profilo immunitario delle cellule tumorali e delle cellule circolanti, per valutare l¿attivit¿ immunomodulante di cabozantinib sull¿immunit¿ tumorale a livello locale e sistemico.

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

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

Yes

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.8.5.1

Number of sites anticipated in the EEA

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

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)

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

2017-11-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-09-25

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

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Orphan Designation Number:
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