Clinical Trials Register

Summary
EudraCT Number:	2014-002497-37
Sponsor's Protocol Code Number:	IOV-SCLC-1-2014-TIMES
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:	2014-10-13
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

2014-002497-37

A.3

Full title of the trial

TIvantinib as Maintenance treatment in Extended Small-cell lung cancer (TIMES)
Phase II clinical trial, single arm, two stage

Tivantinib come terapia di mantenimento nei pazienti con carcinoma polmonare a piccole cellule avanzato (TIMES)
Studio clinico di fase II, a singolo braccio, a due stadi

A.3.1

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

TIvantinib as Maintenance treatment in Extended Small-cell lung cancer

Tivantinib come terapia di mantenimento nel carcinoma polmonare a piccole cellule avanzato

A.3.2

Name or abbreviated title of the trial where available

TIMES

A.4.1

Sponsor's protocol code number

IOV-SCLC-1-2014-TIMES

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 Oncologico del Veneto IRCCS – UOC Oncologia Medica 2
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	AIRC- Italian Cancer Research Association
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	Istituto Oncologico del Veneto IRCCS
B.5.2	Functional name of contact point	UOC Oncologia Medica 2
B.5.3	Address:
B.5.3.1	Street Address	Gattamelata, 64
B.5.3.2	Town/ city	Padova
B.5.3.3	Post code	35128
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390498215608
B.5.5	Fax number	00390498215932
B.5.6	E-mail	giulia.pasello@ioveneto.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	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	Tivantinib
D.3.2	Product code	ARQ197
D.3.4	Pharmaceutical form	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	TIVANTINIB
D.3.9.1	CAS number	905854-02-6
D.3.9.2	Current sponsor code	ARQ 197
D.3.9.3	Other descriptive name	(3R,4R)-3-(5,6-Dihydro-4H-pyrrolo[3,2,1- ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione
D.3.9.4	EV Substance Code	SUB32925
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	120
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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	Yes
D.3.11.13.1	Other medicinal product type	Totally synthetic product

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

Small Cell Lung Cancer (SCLC) after first-line platinum plus etoposide therapy

Carcinoma polmonare a piccole cellule (SCLC) dopo terapia in prima linea con platino e etoposide

E.1.1.1

Medical condition in easily understood language

Lung Cancer

Carcinoma polmonare

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	17.0
E.1.2	Level	PT
E.1.2	Classification code	10041068
E.1.2	Term	Small cell lung cancer extensive stage
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

Evaluate the impact of Tivantinib in increasing the progression free survival (PFS) in the intention to treat (ITT) population

Verificare l'attività di Tivantinib nell’aumentare la sopravvivenza libera da progressione (PFS) nella popolazione ITT

E.2.2

Secondary objectives of the trial

To evaluate overall survival (OS), safety, disease control rate (DCR) in the ITT population.
Additional exploratory objectives include evaluation of quality of life (QoL) in the ITT population, analysis of PFS and OS according to response to the first line treatment and in patients with MET amplification and MET and p-MET overexpression; evaluation of MET pathway dysregulation by analysis of mutations of the genes MET, PIK3CA, AKT, PTEN, RAS, RAF, and MEK; to evaluate acquisition of resistance and molecular changes.

Valutare la sopravvivenza globale (OS), il tasso di controllo della malattia (DCR) e la sicurezza di Tivantinib.
Valutare la qualità di vita (QoL) nella popolazione ITT, analizzare OS e PFS in sottogruppi di pazienti definiti dall’amplificazione MET, dalla sovra-espressione di MET e p-MET, e in base al grado di DCR dopo la prima linea di terapia.
Studiare il pathway di disregolazione del MET mediante analisi dello stato mutazionale dei geni MET, PIK3CA, AKT, PTEN, RAS, RAF e MEK;
valutare l'acquisizione di resistenza e i cambiamenti molecolari

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age ≥ 18 years.
• Histologically confirmed extensive-stage SCLC
• Disease control after the first line platinum/etoposide treatment
• ECOG performance status of 0 or 1
• Measurable disease according to RECIST Version 1.1 criteria
• Adequate bone marrow, liver, and renal function.
• Formalin Fixed Paraffin Embedded (FFPE) or frozen tumor tissue material must be available.
• Resolution of any toxic effects of prior therapy (including radiotherapy) according to NCI CTCAE, version 4.0, ≤ Grade 1 (except for alopecia).
• Full recovery from significant complications of the surgery.
• If childbearing age, use of double-barrier contraceptive measures, oral or abstaining from sexual intercourse during the study and up to 90 days after the last dose of chemotherapy
• Negative pregnancy test within 72 hours prior to the initiation of study treatment, if of childbearing potential
• Signed informed consent prior to beginning protocol specific procedures
• Patients must be available for treatment and follow-up

• Diagnosi istologica di SCLC avanzato
• Età maggiore di 18 anni
• Performance status ECOG 0-1
• Trattamento di prima linea con platino / etoposide per 4-6 cicli con evidenza di risposta completa o parziale o malattia stabile
• Risoluzione di eventuali effetti tossici della precedente terapia (compresa la radioterapia) secondo NCI CTCAE, versione 4.0, Grado ≤ 1 (con l'eccezione di alopecia).
• Recupero completo da significative complicanze della chirurgia.
• Disponibilità di campioni tumorali fissati in formalina ed inclusi in paraffina o congelati per l'analisi di c-MET e di altri geni. Quando possibile, è auspicabile la disponibilità di tessuto congelato per l'analisi di espressione PMET.
• Malattia misurabile secondo RECIST
• Non segni clinici, strumentali e bioumorali di insufficienza midollare, epatica e renale
• Se in età fertile, uso di misure contraccettive a doppia barriera, orali o astensione da rapporti sessuali durante lo studio e fino a 90 giorni dopo l’ultima dose di chemioterapia
• Test di gravidanza negativo per le donne in età fertile entro 72 ore prima dell’inizio del trattamento
• Disponibilità di sottoporsi a follow-up
• Consenso informato scritto

E.4

Principal exclusion criteria

• Clinically unstable central nervous system metastases
• Previous therapies with Tivantinib or other known c-MET inhibitor
• Radiotherapy for target lesions and major surgical procedure within 4 weeks, prior to the inclusion in the study
• Palliative radiotherapy within 2 weeks prior to the inclusion in the study
• History of malignancy in the past five years, excluding basal cell carcinoma of the skin, adequately treated intraepithelial carcinoma of the cervix, prostate cancer with a value of prostate-specific antigen <0.2 ng / mL
• History of cardiac disease
• Known human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infections
• Pregnant or lactating women or childbearing/reproductive potential not using adequate contraception
• Need for breastfeeding during or within 12 weeks of completion of the study
• Gastrointestinal disorders that may interfere with the absorption of Tivantinib
• Inability or unwillingness to swallow the complete doses of Tivantinib
• Any known contraindication to treatment and other significant co-morbid conditions which could jeopardize participation in the study

• Precedente chemioterapia con tivantinib o altri inibitori di MET noti
• Radioterapia palliativa entro 2 settimane prima dell’arruolamento sulle lesioni non target
• Interventi chirurgici maggiori entro 4 settimane prima dell’arruolamento
• Alterata funzione cardiaca
• Necessità di allattamento durante o entro 12 settimane dal completamento dello studio
• Anamnesi positiva per neoplasie negli ultimi cinque anni, ad esclusione del carcinoma basocellulare cutaneo, del carcinoma intraepiteliale del collo dell'utero adeguatamente trattato, del carcinoma prostatico con un valore di antigene prostatico specifico <0,2 ng / mL
• Metastasi del sistema nervoso centrale clinicamente instabili
• Disturbi gastrointestinali significativi che, a giudizio dello sperimentatore, potrebbe interferire con l'assorbimento di tivantinib
• Incapacità o non volontà di ingoiare le dosi complete di tivantinib.
• Qualsiasi controindicazione nota al trattamento e altra significativa condizione di co-morbidità che, a giudizio dello sperimentatore, potrebbe mettere a rischio la partecipazione allo studio
• Infezione nota da virus dell'immunodeficienza umana (HIV), virus dell'epatite B (HBV) o virus dell'epatite C (HCV).

E.5 End points

E.5.1

Primary end point(s)

Progression free survival, assessed from the date of enrolment to the date of disease progression or to the date of death, whichever occurs first

Sopravvivenza libera da progressione dalla data di arruolamento alla data di progressione di malattia o decesso

E.5.1.1

Timepoint(s) of evaluation of this end point

The progression free survival (PFS) will be determined as the time from the date of enrolment to the date of disease progression (or relapse) or to the date of death, whichever occurs first. Patients without a PFS event at the time of analysis will be censored at the date of last assessment.

La PFS sarà valutata come il tempo che intercorre dalla data di arruolamento alla data di progressione della malattia o alla data del decesso, in base a quale vento accada prima. Pazienti senza l'evento PFS al tempo dell'analisi saranno censurati alla data dell'ultima valutazione.

E.5.2

Secondary end point(s)

• Overall survival, assessed from the date of enrolment to the date of death from any cause
• Disease control rate, as percentage of patients achieving a complete response plus partial response plus stable disease
• Toxicity during the treatment, graded according to the NCI-Common Terminology Criteria for Adverse Events (CTCAE) v.4.
• PFS and OS according to type of response to the first-line treatment
• PFS, OS and DCR according to MET amplification and MET and p-MET overexpression, mutations of the genes MET, PIK3CA, AKT, PTEN, RAS, RAF, and MEK using next generation sequencing (NGS) at baseline and at the disease progression
• Quality of Life assessed by EORTC QLQ-C30 and QLQ-LC13

• Sopravvivenza complessiva
• Controllo di malattia, valutata come percentuale di pazienti in risposta obiettiva e malattia stabile
• Numero di copie MET in FISH
• Espressione di MET e pMET in ICH
• Mutazioni di MET, PIK3CA, AKT, PTEN, RAS, RAF, e MEK in NGS
• Qualità della Vita valutata con i questionari EORTC QLQ-C30 e QLQ-C13

E.5.2.1

Timepoint(s) of evaluation of this end point

- The OS will be determined as the time from the date of enrolment to the date of death from any cause. Patients alive at the time of analysis will be censored at the date of last assessment.
- The DCR will be measured from the date of treatment initiation to the date of onset of the first objective response (CR / PR / SD) until the final visit.
- Toxicity will be evaluated during the treatment until 30 days after the last dose of study medication
- Gene mutational status will be analyzed at baseline and at the disease progression date
- The Quality of Life will be assessed from the date of enrollment, every 8 weeks, until the end-of-treatment visit

La Sopravvivenza totale sarà determinata dalla data di arruolamento alla data del decesso per tutte le cause. Pazienti vivi al momento dell’analisi saranno censurati alla data dell’ultima valutazione.
DCR sarà misurata dalla data di inizio trattamento alla data di insorgenza della prima risposta obiettiva (CR/PR/SD) sino all’ultima visita
La tossicità sarà valutata durante il trattamento sino a 30 giorni dopo l'ultima somministrazione del farmaco in studio
Lo stato mutazionale sarà analizzato a livello basale e alla data di progressione
La qualità di vita sarà valutata dalla data di arruolamento, ogni 8 settimane, alla visita di fine trattamento

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

Evaluation of predictive markers of response

Valutazione biomarker predittivi di risposta

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.8.5

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

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

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.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)

None

Nessuno

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

2014-12-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-07-31

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

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