Clinical Trials Register

Summary
EudraCT Number:	2015-001241-84
Sponsor's Protocol Code Number:	CINC280B2201
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-09-10
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

2015-001241-84

A.3

Full title of the trial

A phase Ib/II, open-label, multicenter trial with oral cMET inhibitor INC280 alone and in combination with erlotinib versus platinum/pemetrexed in adult patients with EGFR mutated, cMETamplified,
locally advanced/metastatic nonsmall cell lung cancer (NSCLC) with acquired resistance to prior EGFR tyrosine kinase inhibitor (EGFR TKI)

Studio di Fase Ib/II, in aperto, multicentrico, con INC280 inibitore di cMET per via orale in monoterapia e in associazione a erlotinib verso platino/pemetrexed, in pazienti adulti con carcinoma polmonare non a piccole cellule (NSCLC) con mutazione di EGFR, cMET amplificato, in stadio localmente avanzato/metastatico con resistenza acquisita alla terapia precedente con inibitore della tirosinchinasi di EGFR (EGFR TKI)

A.3.1

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

Study of safety and efficacy of INC280 alone, and in combination with erlotinib, compared to chemotherapy, in advanced/metastatic non-small
cell lung cancer patients with EGFR mutation and cMET amplification

Studio dell’efficacia e della sicurezza d’impiego di INC280 in monoterapia e in associazione a erlotinib, in confronto alla chemioterapia, in pazienti con carcinoma polmonare non a piccole cellule (NSCLC) con mutazione di EGFR e amplificazione di cMET in stadio avanzato/metastatico

A.3.2

Name or abbreviated title of the trial where available

Study of INC280 alone and in combination with erlotinib vs. chemotherapy

Studio di INC280 da solo ed in combinazione con erlotinib vs. chemioterapia in NSCLC con EGFR+ ed am

A.4.1

Sponsor's protocol code number

CINC280B2201

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	NOVARTIS FARMA S.P.A.
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Farma S.p.A.
B.5.2	Functional name of contact point	Drug Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	Largo Umberto Boccioni, 1
B.5.3.2	Town/ city	Origgio (VA)
B.5.3.3	Post code	21040
B.5.3.4	Country	Italy
B.5.4	Telephone number	0296541
B.5.5	Fax number	029659066
B.5.6	E-mail	info.studiclinici@novartis.com

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	INC280
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	capmatinib
D.3.9.1	CAS number	1197376-85-4
D.3.9.2	Current sponsor code	INC280
D.3.9.4	EV Substance Code	SUB31645
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	100
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.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	Yes
D.2.1.1.1	Trade name	Tarceva
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Reg. Ltd
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	ERLOTINIB CLORIDRATO
D.3.9.1	CAS number	183319-69-9
D.3.9.2	Current sponsor code	NA
D.3.9.4	EV Substance Code	SUB21050
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	25 to 150
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.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	Alimta
D.2.1.1.2	Name of the Marketing Authorisation holder	Eli Lilly Nederland BV
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Powder for 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	PEMETREXED DISODICO
D.3.9.1	CAS number	150399-23-8
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	PEMETREXED DISODIUM
D.3.9.4	EV Substance Code	SUB03669MIG
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	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.IMP: 4
D.1.2 and D.1.3	IMP Role	Comparator
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	Cisplatino
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Italia S.r.l.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Cisplatino
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	CISPLATINO
D.3.9.2	Current sponsor code	CISPLATINO
D.3.9.3	Other descriptive name	CISPLATIN
D.3.9.4	EV Substance Code	SUB07483MIG
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	1
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.IMP: 5
D.1.2 and D.1.3	IMP Role	Comparator
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	Carboplatino
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA PHARMA B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	CARBOPLATINO
D.3.2	Product code	NA
D.3.4	Pharmaceutical form	Concentrate for 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	CARBOPLATINO
D.3.9.2	Current sponsor code	CARBOPLATINO
D.3.9.3	Other descriptive name	CARBOPLATIN
D.3.9.4	EV Substance Code	SUB06614MIG
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	10
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

Non-small cell lung cancer

Cancro dei polmoni non a piccole cellule

E.1.1.1

Medical condition in easily understood language

Lung cancer

Cancro dei polmoni

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	PT
E.1.2	Classification code	10061873
E.1.2	Term	Non-small cell lung cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10059515
E.1.2	Term	Non-small cell lung cancer metastatic
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

Phase Ib: To determine MTD and/or RP2D of INC280 in combination with erlotinib
Phase II: To compare the antitumor activity of INC280 alone, and INC280 in combination with erlotinib, vs platinum with pemetrexed, as
measured by Progression Free Survival (PFS) per investigator's assessment

Fase Ib: Determinare la MTD e/o la RP2D di INC280 in associazione a erlotinib
Fase II: Confrontare l’attività antitumorale di INC280 in monoterapia e di INC280 in associazione a erlotinib, verso platino in associazione a pemetrexed, valutata mediante la sopravvivenza libera da progressione (PFS), in base alla valutazione dello sperimentatore.

E.2.2

Secondary objectives of the trial

Phase Ib:
¿ To assess the antitumor activity of INC280 in combination with erlotinib, as measured by overall response rate (ORR), disease control rate (DCR), duration of response (DOR) and PFS per investigator's assessment
¿ To evaluate overall survival (OS)
¿ To determine safety and tolerability of INC280 in combination with erlotinib
¿ To characterize the PK of INC280 in the presence of erlotinib
¿ To characterize the PK of erlotinib in the presence of INC280
Phase II:
¿ To assess the antitumor activity of INC280 alone, and INC280 in combination with erlotinib, vs. platinum with pemetrexed, as measured
by ORR, DCR, and DOR per Investigator's assessment
¿ To evaluate OS
¿ To determine safety and tolerability of the combination of INC280 and erlotinib and of INC280 single agent

Fase Ib:
¿¿ Valutare l’attività antitumorale di INC280 in associazione a erlotinib, misurata mediante il tasso di risposta globale (ORR), il tasso di controllo della malattia (DCR), la durata della risposta (DOR) e la sopravvivenza libera da progressione (PFS), in base alla valutazione dello sperimentatore.
¿¿ Valutare la sopravvivenza globale (OS).
¿¿ Determinare la sicurezza d’impiego e la tollerabilità di INC280 in associazione a erlotinib.
¿¿ Caratterizzare la farmacocinetica di INC280 in presenza di erlotinib.
¿¿ Caratterizzare la farmacocinetica di erlotinib in presenza di INC280.
Fase II:
¿¿ Valutare l’attività antitumorale di INC280 in monoterapia e di INC280 in associazione a erlotinib, verso platino con pemetrexed, misurata mediante ORR, DCR e DOR, in base alla valutazione dello sperimentatore.
¿¿ Valutare la sopravvivenza globale (OS).
¿¿ Determinare la sicurezza d’impiego e la tollerabilità di INC280 in associazione a erlotinib.
¿

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Specific for Phase Ib:
¿ Patients must have received at least one line of systemic therapy, including one prior 1st generation (e.g., erlotinib, gefitinib) or 2nd generation (e.g., afatinib) EGFR TKI; any line of prior systemic
chemotherapy is allowed
¿ Molecular pre-screening assessment:
¿ cMET-amplification (GCN = 6) by FISH assessed from a biopsy or an archival tumor sample collected at or any time after the progression on prior 1st or 2nd generation EGFR TKI, determined locally or by a
Novartis-designated central laboratory
¿ Patients with known EGFRT-790M mutation are not eligible
¿ Patients must have at the screening visit: Platelet count = 75 x 109/L
Specific for Phase II:
¿ Patients must have received one and only one prior line of 1st generation (e.g., erlotinib, gefitinib) or 2nd generation (e.g., afatinib) EGFR TKI for the treatment of locally advanced or metastatic NSCLC
¿ No prior chemotherapy is allowed, except:
¿ Patients, who switched from platinum-based chemotherapy to EGFR TKI during first line treatment within 28 days since the start date of
chemotherapy, will be allowed to enter the study, in the absence of disease progression
¿ Prior neoadjuvant/adjuvant cytotoxic chemotherapy is not allowed, unless the relapse occurred more than 12 months after the last
administration of neoadjuvant/adjuvant chemotherapy
¿ Molecular pre-screening assessment:
¿ cMET-amplification (GCN = 6) by FISH determined by a Novartis designated central laboratory on a newly obtained tumor biopsy
(preferred) or an archival tumor sample obtained at or any time after the progression on prior 1st or 2nd generation EGFR TKI
¿ EGFR-T790M negative status assessed from a biopsy or an archival tumor sample collected at or any time after the progression on prior 1st or 2nd generation EGFR TKI, determined locally by either Roche Cobas or Qiagen therascreen test or by a Novartis designated central laboratory
¿ Presence of at least one measurable lesion according to RECIST v1.1. A previously irradiated site lesion may only be counted as a target lesion if
there is clear sign of progression since the irradiation.
¿ Patients must have at the screening visit:
¿ White blood cell count = 4 x 109/L
¿ Platelet count = 100 x 109/L
Common for Phase Ib and Phase II:
¿ = 18 years of age at the time of informed consent.
¿ Locally advanced or metastatic NSCLC (stage IIIB and is not a candidate for definitive multimodality therapy or IV) other than predominantly squamous cell histology harboring EGFR mutation known
to be associated with EGFR TKI drug sensitivity (exon 19 deletion or L858R).
¿ Patients must meet the criteria for acquired resistance to EGFR TKI (either 1st generation (e.g., erlotinib, gefitinib) or 2nd generation (e.g.,
afatinib)) defined as: Documented clinical benefit (CR, PR, or SD (= 6 months) as per RECIST) or Demonstrated progression, while on continuous treatment, or within 30 days since the date of last
administration of EGFR TKI, per RECIST
¿ Patients must have recovered from all toxicities related to prior anticancer therapies to grade = 1 (CTCAE v 4.03). Patients with any grade of alopecia are allowed to enter the study.
¿ Life expectancy = 3 months
¿ ECOG performance status (PS) = 1.
¿ Patients must have at the screening visit:
¿ Hemoglobin = 9 g/dL
¿ Absolute neutrophil count (ANC) = 1.5 x 109/L
¿ Calculated creatinine clearance (using Cockcroft-Gault formula) > 45 mL/min
¿ Total bilirubin = 1.5 x ULN, except for patients with Gilbert's syndrome, who may only be included if total bilirubin = 3.0 x ULN or direct bilirubin = 1.5 x ULN
¿ Aspartate transaminase (AST) = 3 x ULN, except for patients with liver metastasis, who are only included if AST = 5 x ULN
¿ Alanine transaminase (ALT) = 3 x ULN, except for patients with liver metastasis, who are only included if ALT = 5 x ULN
¿ Fasting plasma glucose = 175 mg/dL (= 9.8 mmol/L)
¿ Alkaline phosphatase (ALP) = 5.0 x ULN

Specifici per Fase Ib:
¿ I pazienti devono aver ricevuto almeno una linea di terapia sistemica, comprendente una terapia precedente di prima generazione (ad esempio erlotinib, gefitinib) o una terapia precedente di seconda generazione (ad esempio afatinib) con EGFR TKI; sarà consentita qualsiasi linea di chemioterapia sistemica precedente.
2. Valutazioni di pre-screening molecolare:
¿ Amplificazione di c-MET (GCN > 6) valutata mediante FISH in un campione raccolto mediante biopsia o un campione di tessuto tumorale archiviato, prelevato alla progressione o in qualsiasi momento dopo la progressione durante terapia precedente con EGFR TKI di prima o di seconda generazione, determinata localmente o da un laboratorio centralizzato designato da Novartis.
¿ I pazienti con mutazione nota in EGFRT790M non sono eleggibili.
3. I pazienti devono presentare alla visita di screening: Piastrine > 75 x 109/L
Specifici per la Fase II:
¿ I pazienti devono aver ricevuto una e solamente una linea precedente di EGFR TKI di prima generazione (ad esempio erlotinib, gefitinib) o una terapia precedente di seconda generazione (ad esempio afatinib) per il trattamento del NSCLC in stadio localmente avanzato o metastatico.
¿ Non è consentita alcuna chemioterapia precedente, a eccezione delle seguenti circostanze:
¿ I pazienti che sono passati dalla chemioterapia a base di platino alla terapia con EGFR TKI durante il trattamento di prima linea entro 28 giorni dalla data di inizio della chemioterapia, potranno entrare nello studio, in assenza di progressione della malattia
¿ Non sarà consentita la chemioterapia citotossica neoadiuvante/adiuvante precedente, a meno che la recidiva non si sia manifestata oltre i 12 mesi dopo l’ultima somministrazione della chemioterapia neoadiuvante/adiuvante.
¿ Valutazioni di pre-screening molecolare:
¿ Amplificazione di c-MET (GCN > 6) valutata mediante FISH da un laboratorio centralizzato designato da Novartis in un campione raccolto mediante una biopsia eseguita allo scopo (preferibile) o un campione di tessuto tumorale archiviato prelevato al momento della progressione o in qualsiasi momento dopo la progressione durante terapia con EGFR TKI di prima o di seconda generazione ¿
¿ Status EGFRT790M negativo valutato in una biopsia o su un campione tumorale archiviato prelevato al momento della progressione o in qualsiasi momento dopo la progressione durante terapia con EGFR TKI di prima o di seconda generazione, determinato localmente dal test “Roche Cobas” o dal test “Qiagen therascreen” o da un laboratorio centralizzato designato da Novartis.
¿ Presenza di almeno una lesione misurabile, definita in base ai criteri RECIST 1.1. Una sede di lesione precedentemente irradiata può essere calcolata solo come una lesione target se vi è un chiaro segno di progressione dal momento dell’irradiazione.
¿ I pazienti devono presentare alla visita di screening:
¿ Piastrine > 100 x 109/L
¿ Conta leucocitaria > 4 x 109/L
Comuni alla Fase Ib e alla Fase II:
¿ Età > 18 anni al momento del consenso informato.
¿ NSCLC in stadio localmente avanzato o metastatico (stadio IIIB e non candidato alla terapia multimodale definitiva o IV), diverso da istologia a cellule squamose prevalenti, con mutazioni di EGFR che si associano alla sensibilità ai farmaci EGFR TKI (delezione dell’esone 19 o L858R).
¿ I pazienti devono soddisfare i criteri per la resistenza acquisita a EGFR TKI (sia di prima generazione, ossia erlotinib, gefitinib, sia di seconda generazione, ossia afatinib) definiti da: beneficio clinico documentato (CR, PR o SD > 6 mesi in base a RECIST). Progressione dimostrata durante il trattamento continuativo o entro 30 giorni dalla data dell’ultima somministrazione di EGFR TKI, in base a RECIST.
¿ I pazienti devono aver presentato risoluzione di tutte le tossicità correlate alle terapie antitumorali precedenti a Grado < 1 (CTCAE v 4.03). Ai pazienti con qualsiasi grado di alopecia è consentito entrare nello studio.
¿ Speranza di vita > 3 mesi.
¿ ECOG Performance Status (PS) < 1.
¿ I pazienti devono presentare alla visita di screening:
¿ Emoglobina > 9 g/dL
¿ Conta neutrofila assoluta (ANC) > 1,5 x 109/L
¿ Clearance della creatinina calcolata (utilizzando la formula di Cockcroft-Gault) > 45 mL/min
¿ Bilirubinemia totale < 1,5 x ULN, a eccezione dei pazienti con sindrome di Gilbert che possono essere inclusi solo se la bilirubina totale è < 3,0 x ULN o la bilirubina diretta è < 1,5 x ULN.
¿ Aspartato aminotrasferasi (AST) < 3 x ULN a eccezione dei pazienti con metastasi epatiche, che possono essere inclusi solo se AST è < 5 x ULN.
¿ Alanina aminotrasferasi (ALT) < 3 x ULN a eccezione dei pazienti con metastasi epatiche, che possono essere inclusi solo se ALT è < 5 x ULN.
¿ Glicemia a digiuno < 175 mg/dL (< 9,8 mmol/L)
¿ Fosfatasi alcalina (ALP) < 5,0 x ULN.

E.4

Principal exclusion criteria

Specific Phase II:
¿ Patients with history of severe hypersensitivity reaction to platinum containing drugs, pemetrexed or any known excipients of these drugs.
¿ Prior treatment with any of the following agents
¿ Crizotinib, or any other cMET inhibitor or HGF-targeting inhibitor.
¿ Concomitant EGFR TKI and platinum based chemotherapy as first line regimen.
¿ Platinum-based chemotherapy as first line treatment.
Common for Phase Ib and Phase II:
¿ Prior treatment with any 3rd generation EGFR TKI (e.g., CO1686, AZD9192).
¿ Symptomatic central nervous system (CNS) metastases
¿ Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention).
¿ Presence of clinically significant ophthalmologic abnormalities
¿ Strong inhibitors or moderate inducers of CYP3A4; strong inducers of CYP3A4; strong inhibitors or strong inducers of CYP1A2; proton pump inhibitors, within 1 week prior to start of treatment with INC280 and for the duration of the study
¿ Pregnant or nursing women

Specifici per la Fase II:
¿ Pazienti con un’anamnesi positiva per reazione di ipersensibilità grave ai farmaci contenenti platino, pemetrexed o qualsiasi eccipiente noto di questi farmaci.
¿ Trattamento precedente con uno dei seguenti farmaci:
¿¿ Crizotinib o qualsiasi altro inibitore di cMET o inibitore con target HGF.
¿¿ Chemioterapia con EGFR TKI e platino in concomitanza, come regime di prima linea.
¿¿ Chemioterapia a base di platino, come trattamento di prima linea.
Comuni alla Fase Ib e alla Fase II:
¿ trattamento precedente con qualsiasi EGFR TKI di terza generazione (ad esempio CO1686, AZD9192, EGF816).
¿ Pazienti con metastasi sintomatiche del sistema nervoso centrale (SNC)
¿ Evidenza attuale o pregressa di malattia interstiziale polmonare o polmonite interstiziale, compresa la polmonite da radiazioni clinicamente rilevante (ossia che compromette le attività della vita quotidiana o richiede intervento terapeutico).
¿ Presenza di alterazioni oftalmologiche clinicamente rilevanti
¿ Inibitori forti e moderati di CYP3A4; Induttori forti di CYP3A4; inibitori forti o induttori forti di CYP1A2; inibitori della pompa protonica, entro 1 settimana prima dell'inizio del trattamento con INC280 e per tutta la durata dello studio
¿ Donne incinte o in allattamento

E.5 End points

E.5.1

Primary end point(s)

Phase Ib: Frequency and characteristics of DLTs to the INC280 and erlotinib combination
Phase II: PFS, defined as time from randomization to progression or death due to any cause, by investigator's assessment according to RECIST v1.1

Fase Ib: Frequenza e caratteristiche del DLT alla combinazione di INC280 ed erlotinib
Fase II: PFS, definita come il tempo dalla randomizzazione alla progressione o morte dovuta a qualsiasi causa, per la valutazione dello sperimentatore in accordo al RECIST v1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

As defined per protocol

Come definito dal protocollo

E.5.2

Secondary end point(s)

Phase Ib:
¿ ORR, DCR, DOR, PFS by investigator's assessment according to RECIST v1.1
¿ OS
¿ Incidence of adverse events and serious adverse events, change in vital signs, laboratory results and ECG
¿ Plasma concentration-time profiles and pharmacokinetic parameters of INC280 and of erlotinib
Phase II:
¿ ORR, DCR, DOR by investigator's assessment according to RECIST v1.1
¿ OS
¿ Incidence of adverse events and serious adverse events, change in vital signs, laboratory results and ECG
¿ Plasma concentrations of INC280
¿ Plasma concentrations of erlotinib

Fase Ib:
¿ ORR, DCR, DOR, PFS per la valutazione dello sperimentatore secondo RECIST v1.1
¿ OS
¿ Incidenza degli eventi avversi e degli eventi seri, cambiamenti nei segni vitali, risultati di laboratorio ed ECG
¿ Profili del plasma concentrazione-tempo e parametri farmacocinetici di INC280 e di erlotinib
Fase II:
¿ ORR, DCR, DOR, per la valutazione dello sperimentatore secondo RECIST v1.1
¿ OS
¿ Incidenza degli eventi avversi e degli eventi seri, cambiamenti nei segni vitali, risultati di laboratorio ed ECG
¿ Concentrazione plasmatica di INC280
¿ Concentrazione plasmatica di erlotinib

E.5.2.1

Timepoint(s) of evaluation of this end point

As defined per protocol

Come definito dal protocollo

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

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

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

Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D) dose escalation

Massima Dose Tollerata (MTD) e/o Dose raccomandata per la Fase II (RP2D) aumento della dose

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

to determine the MTD or the RP2D of INC280 in combination with erlotinib

determinare la MTD o la RP2D di INC280 in associazione a erlotinib

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

Yes

E.8.1.1

Randomised

Yes

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

Yes

E.8.1.7.1

Other trial design description

Fase Ib/II

Phase Ib/Phase II

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

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

Yes

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Brazil

Canada

India

Israel

Japan

Korea, Democratic People's Republic of

Russian Federation

Singapore

Turkey

United States

Belgium

France

Germany

Hungary

Italy

Netherlands

Portugal

Spain

Sweden

E.8.7

Trial has a data monitoring committee

Yes

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

The end of study defined as the earliest occurrence of the following:
• All patients have died or discontinued from the study
• Another clinical study becomes available that can continue to provide INC280 in this patient population and all patients ongoing are eligible to be transferred to that clinical study
• INC280 is commercially available and ongoing patients are able to obtain reimbursement of commercial supply

La fine dello studio è definita come il primo avvenimento tra i seguenti:
• Tutti i pazienti sono deceduti o hanno interrotto lo studio
• Si è reso disponibile un altro studio clinico che può continuare a fornire INC280 in questa popolazione di pazienti e tutti i pazienti ongoing sono eleggibili per essere trasferiti in questo studio.
• INC280 è commercialmente disponibile ed i pazienti ongoing sono in grado di ottenerne il rimborso

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

135

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)

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

2015-09-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-09-09

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-12-05

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