Clinical Trials Register

Summary
EudraCT Number:	2018-000582-36
Sponsor's Protocol Code Number:	BREAKPOINT
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-01-05
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-000582-36

A.3

Full title of the trial

A phase 2 open label study of caBozantinib in patients with advanced or unresectable Renal cEll cArcinoma pretreated with one immunochecKPOint INhibiTor (anti PD1/PDL1)

Studio di fase 2 in aperto con Cabozantinib in pazienti affetti da carcinoma renale avanzato o metastatico pretrattati con una linea di trattamento con inibitore degli immunochecKPOints (anti PD1/PDL1)

A.3.1

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

A phase 2 open label study of caBozantinib in patients with advanced or unresectable Renal cEll cArcinoma pretreated

Studio di fase 2 in aperto con Cabozantinib in pazienti affetti da carcinoma renale avanzato o metastatico pretrattati

A.3.2

Name or abbreviated title of the trial where available

BREAKPOINT

A.4.1

Sponsor's protocol code number

BREAKPOINT

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:

BREAKPOINT

Number:

BREAKPOINT

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	0223903817
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.3.1	Product name	CABOZANTINIB
D.3.2	Product code	[CABOZANTINIB]
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

Patients with metastatic clear cell renal cell carcinoma pretreated with immunocheckpoints inhibitors

Pazienti affetti da carcinoma renale metastatico pretrattati con una precedente linea con inibitori degli immunocheckpoints

E.1.1.1

Medical condition in easily understood language

metastatic clear cell carcinoma pretreated

tumore del rene avanzato in progressione a una precedente terapia

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	PT
E.1.2	Classification code	10073251
E.1.2	Term	Clear cell renal cell carcinoma
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

Assess the progression free survival (PFS) of cabozantinib in patients pretreated with one immunocheckpoint inhibitor (CPI) in monotherapy or in combination

Valutazione della Sopravvivenza libera da progressione (PFS) di cabozantinib in pazienti pretrattati con un inibitore degli immunocheckpoint in monoterapia o in combinazione

E.2.2

Secondary objectives of the trial

•Assess the overall survival (OS)
•Evaluate the efficacy based on objective response rates (ORR) according to RECIST 1:1 criteria
•Characterize the safety profile of the drug

• Sopravvivenza Globale (OS)
• Tasso di risposte obiettive (ORR) in accordo con i criteri RECIST 1.1.
• Profilo di tossicità del farmaco

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Signed written informed consent
2.One previous anticancer treatment with a PD1/PDL1 inhibitor, as monotherapy or in combination with an angiogenesis inhibitor or anti CTLA 4, in both setting first line or adjuvant ( in this case patient having recurrence during the adjuvant treatment or within 6 months after therapy with PD1-PD-L1 therapy)
3.Age =18 years
4.Patients with histological diagnosis of predominant clear cells renal cell carcinoma
5.Measurable disease (as per RECIST 1.1 criteria) with documented radiological progression
6.Fertile women (<2 years after last menstruation) and men of childbearing potential must use effective methods of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgical sterilisation) during the study and for 4 months after the last dose of study treatment
7.All sites of disease including brain metastases (non symptomatic)
8.Karnofsky performance status = 70%
9.Life expectancy greater than 3 months
10.The required values at baseline are as follows:
-Absolute neutrophil count >1.5 x 109 /L,
-Platelet count > 100 x 109 /L,
-Haemoglobin > 9g/dl,
-Total bilirubin < 1.5 upper limit of normal (ULN);
-AST, ALT<2.5 ULN in patients without liver metastases, <5 ULN in patients with liver metastases;
-serum creatinine < 2.0 mg/dl, amylase and lipase <1.5 ULN
11. Female subjects of childbearing potential must not be pregnant at screening

1.Consenso informato scritto
2.Un precedente trattamento con inibitori di PD1-PDL1 usati in monoterapia o in combinazione con un inibitore dell’angiogenesi o un anti CTLA4 in setting di prima linea o adiuvante (in questo caso il paziente deve avere una ripresa di malattia durante il trattamento adiuvante o entro i 6 mesi dalla fine del trattamento)
3.Età > 18 anni
4.Diagnosi istologica di carcinoma renale con predominanza istologica a cellule chiare
5.Almeno una lesione misurabile (secondo criteri RECIST 1.1) con evidenza di progressione radiologica
6.Donne e uomini in età fertile devono usare metodi contraccettivi efficaci (contraccettivi orali, dispositivi contraccettivi intrauterini, metodi contraccettivi di barriera associati a gel spermicidi o sterilizzazione chirurgica) per tutta la durata del trattamento e per almeno 4 mesi dopo l’interruzione del trattamento.
7.Sono ammesse tutte le sedi di malattia, incluse le metastasi cerebrali ammesso che non siano sintomatiche
8.Karnofsky performance status = 70%
9.Aspettativa di vita superiore ai 3 mesi
10.Valori di laboratorio basali compatibili con il protocollo come segue:
-Conta assoluta di neutrofili >1.5 x 109/L,
-Conta piastrinica > 100 x 109/L,
-Emoglobina > 9g/dl,
-Bilirubina totale < 1.5 al limite superiore di normalità (ULN);
-AST, ALT<2.5 al limite superiore di normalità (ULN) in pazienti senza metastasi epatiche, <5 ULN al limite superiore di normalità (ULN) in pazienti con metastasi epatiche, creatinina sierica < 2.0 mg/dl, amilasi e lipasi <1.5 al limite superiore di normalità (ULN)
11. Le donne in età fertile non devono essere in gravidanza allo screening

E.4

Principal exclusion criteria

1.Major surgical procedure within 28 days prior to study treatment start
2.Other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix, meningiomas)
3.Clinically significant cardiovascular disease, for example cerebrovascular accidents (<6 months), myocardial infarction (<6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure or serious cardiac arrhythmia requiring medication
4.Recent (within the 30 days prior to randomisation) treatment with another investigational drug or participation in another investigational study
5.Symptomatic brain metastasis
6.History of other disease, metabolic dysfunction, physical examination finding or clinical laboratory finding giving reasonable suspicion of a disease condition that contraindicates use of an investigational drug or patient at high risk from treatment complications
7.PT or INR and PTT >1.5 times the Upper Normal Limit of the institution (patient who are being therapeutically anticoagulated with an agent such as warfarin 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
8.Previous or concomitant radiotherapy in the lesion parameter of disease
9.Previous radiotherapy or other locoregional antitumoral treatment performed within 21 days before the study recruitment
10.Uncontrolled hypertension (>= 160 mmHg systolic and/or 90 mmHg diastolic) while receiving chronic medication
11. Inability to swallow tablets or capsules
12.Female subject who is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum ß-human chorionic gonadotropin (ß-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women
13.Known history of human immunodeficiency virus (HIV) infection, active hepatitis B, or active hepatitis C.
14.Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption

1.Procedure di chirurgia maggiore nei 28 giorni precedenti all’inizio del farmaco da studio
2.Altra patologia oncologica diagnosticata negli ultimi 5 anni (eccetto che per carcinomi basocellulari della cute e/o carcinoma in situ della cervice, meningiomi)
3.Malattie cardiovascolari clinicamente rilevanti, come eventi cerebrovascolari (<6mesi), infarto del miocardio (<6 mesi), angina instabile, scompenso cardiaco congestizio o aritmia cardiaca seria che richiede trattamenti
4.Recente trattamento con un altro farmaco da studio (entro i 30 giorni dall’inizio del trattamento)
5.Metastasi cerebrali sintomatiche
6.Anamnesi di altre patologie, disfunzioni metaboliche o evidenze all’esame obiettivo o di laboratorio che controindichino l’utilizzo del farmaco in studio o pongano il paziente ad alto rischio di sviluppare complicanze
7.PT o INR e PTT >1.5 volte il limite superiore (i pazienti in terapia anticoagulante con agenti come il warfarin o eparina non possono essere inclusi nello studio se non vengono escluse prima anomalie in questi parametri di laboratorio. Per i pazienti in terapia con farfari è raccomandato uno stretto monitoraggio, almeno settimanale dei parametri di coagulazione.
8.Precedente radioterapia nella lesione parametro di malattia
9.Precedente radioterapia o altro trattamento loco regionale nei 21 giorni precedenti all’inizio del trattamento
10.Ipertensione arteriosa non controllata durante una terapia medica specifica (>= 160 mmHg sistolica e/o >= 90 mmHg diastolica)
11.Incapacità a deglutire compresse o capsule
12.Donne in stato di gravidanza o durante la fase di allattamento.La conferma che la paziente non sia incinta deve essere confermata da un risultato negativo del test di gravidanza su siero ß-gonadotropina corionica (ß-hCG) ottenuto durante lo screening. Il test di gravidanza non è richiesto per le donne in post-menopausa o sterilizzate chirurgicamente
13.Storia conosciuta di infezione da HIV , epatite B o epatite C
14.Problemi ereditari di intolleranza al galattosio, deficit di Lapp lattasi o malassorbimento di glucosio-galattosio

E.5 End points

E.5.1

Primary end point(s)

Progression Free Survival (PFS)

Sopravvivenza Libera da Progressione (PFS)

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)

Overall Survival (OS); Objective Response Rates (ORR) ; Safety profile of the drug

Sopravvivenza Globale (OS); Tasso di Risposte Obiettive (ORR); Profilo di tossicità del farmaco

E.5.2.1

Timepoint(s) of evaluation of this end point

duration of the study; duration of the study; duration of the study

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

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

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

2018-05-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-03-20

P. End of Trial
P.	End of Trial Status	Trial now transitioned

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials