Clinical Trials Register

Summary
EudraCT Number:	2020-003677-21
Sponsor's Protocol Code Number:	CINC280L12301
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-04-22
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

France - ANSM

A.2

EudraCT number

2020-003677-21

A.3

Full title of the trial

A phase III randomized, controlled, open-label, multicenter, global study of capmatinib in combination with osimertinib versus platinum - pemetrexed based doublet chemotherapy in patients with locally advanced or metastatic NSCLC harboring EGFR activating mutations who have progressed on prior 1st/2nd generation EGFR-TKI or osimertinib therapy and whose tumors are T790M mutation negative and harbor MET amplification (GEOMETRY-E)

Etude de phase III, randomisée, contrôlée, en ouvert, évaluant l’association capmatinib-osimertinib versus la chimiothérapie à base de platinepemetrexed chez des patients atteints d'un cancer du poumon non à petites cellules localement avancé ou métastatique EGFR muté ayant progressé après traitement par un inhibiteur EGFR (ITK EGFR) de 1ère/2ème génération ou par osimertinib et ayant une amplification MET (GEOMETRY-E)

A.3.1

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

Study of safety and efficacy of capmatinib in combination with osimertinib compared to platinum - pemetrexed based doublet chemotherapy in patients with locally advanced or metastatic non-small cell lung cancer harboring EGFR activating mutations and T790M negative who have progressed on prior EGFR-TKI therapy

Etude de la sécurité et de l'efficacité évaluant l’association capmatinib-osimertinib versus la chimiothérapie à base de platinepemetrexed chez des patients atteints d'un cancer du poumon non à petites cellules localement avancé ou métastatique EGFR muté ayant progressé après traitement par un inhibiteur EGFR (ITK EGFR)

A.4.1

Sponsor's protocol code number

CINC280L12301

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 Pharma AG
B.1.3.4	Country	Switzerland
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 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 Pharma S.A.S
B.5.2	Functional name of contact point	Information&Communication Médicales
B.5.3	Address:
B.5.3.1	Street Address	8/10 rue Henry Sainte Claire Deville, CS 40150
B.5.3.2	Town/ city	Rueil-Malmaison
B.5.3.3	Post code	92563
B.5.3.4	Country	France
B.5.4	Telephone number	+33 1 5547 6600
B.5.5	Fax number	+33 1 5547 6100
B.5.6	E-mail	icm.phfr@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	capmatinib
D.3.2	Product code	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	1865733-40-9
D.3.9.2	Current sponsor code	INC280
D.3.9.3	Other descriptive name	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	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	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	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.2.5	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	Osimertinib
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	OSIMERTINIB
D.3.9.1	CAS number	1421373-65
D.3.9.2	Current sponsor code	AZD 9291
D.3.9.4	EV Substance Code	SUB12492MIG
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	80
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	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.2.5	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	pemetrexed
D.3.4	Pharmaceutical form	Powder for 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	PEMETREXED
D.3.9.1	CAS number	137281-23-3
D.3.9.4	EV Substance Code	SUB31645
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	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	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.2.5	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	cisplatin
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	CISPLATIN
D.3.9.1	CAS number	15663-27-1
D.3.9.4	EV Substance Code	SUB31645
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	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	No
D.IMP: 5
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	capmatinib
D.3.2	Product code	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	1865733-40-9
D.3.9.2	Current sponsor code	INC280
D.3.9.3	Other descriptive name	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	200
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	No
D.IMP: 6
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.2.5	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	carboplatin
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	CARBOPLATIN
D.3.9.1	CAS number	41575-94-4
D.3.9.4	EV Substance Code	SUB31645
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	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	No
D.IMP: 7
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.2.5	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	Osimertinib
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	OSIMERTINIB
D.3.9.1	CAS number	1421373-65
D.3.9.2	Current sponsor code	AZD 9291
D.3.9.4	EV Substance Code	SUB12492MIG
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.3.11 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	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

EGFR mutated, T790M negative NSCLC

La mutation EGFR, CBNPC T790M négatif

E.1.1.1

Medical condition in easily understood language

Type of lung cancer, called non-small cell lung cancer (NSCLC) with certain genetic alterations (called mutations) of a gene called epidermal growth factor receptor (EGFR)

Cancer broncho-pulmonaire non à petites cellules (CBNPC) avec mutation activatrice du récepteur du facteur de croissance épidermique (EGFR)

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.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Run-in part: to confirm the recommended dose of capmatinib in combination with osimertinib for the randomized part

Randomized part: to compare the progression-free survival (PFS) of capmatinib in combination with osimertinib versus platinum-based doublet chemotherapy

Partie Run-in
Confirmer la dose recommandée de l’association capmatinib-osimertinib pour la partie randomisée

Partie randomisée
Comparer la survie sans progression (SSP) de l’association capmatinib-osimertinib à celle du traitement platine-pemetrexed

E.2.2

Secondary objectives of the trial

Key secondary objective:

To compare the Overall Response Rate (ORR) of capmatinib in combination with osimertinib

To compare the overall intracranial response rate (OIRR) of capmatinib in combination with osimertinib

Other secondary objectives:

To characterize the safety and tolerability of capmatinib in combination with osimertinib

To characterize the pharmacokinetics of capmatinib, osimertinib, and osimertinib's active metabolites (AZ5104 and AZ7550)

To assess the tumor response of capmatinib in combination with osimertinib

To assess PFS2 (PFS after next-line of treatment)

To evaluate the association between MET amplification status as measured in ctDNA at baseline with PFS and ORR

To evaluate overall survival (OS) in participants treated with capmatinib in combination with osimertinib

To evaluate the safety profile of capmatinib in combination with osimertinib

To assess intracranial anti-tumor activity of capmatinib in combination with osimertinib

Objectifs Secondaires clés

Evaluer le taux de réponse global (ORR) de l’association capmatinib-osimertinib
Evaluer le taux de réponse global intracrânienne (OIRR), de l’association capmatinib-osimertinib

Autres objectifs Secondaires

Evaluer le profil de tolérance et l’innocuité de l’association capmatinib-osimertinib
Caractériser le profil pharmacocinétique de capmatinib, osimertinib et des métabolites actifs de l'osimertinib (AZ5104 et AZ7550)
Evaluer la réponse tumorale de l’association capmatinib-osimertinib
Evaluer SSP2 (a survie sans progression sous la 2ème ligne de traitement)
Evaluer la relation entre le statut d'amplification de MET tel que mesuré dans l'ADNct à la baseline et la SSP et l'ORR
Evaluer la survie globale (SG) des patients traités par l’association capmatinib-osimertinib
Evaluer le profil de tolérance de l’association capmatinib-osimertinib
Evaluer l'activité antitumorale intracrânienne de l’association capmatinib-osimertinib

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed informed consent must be obtained prior to participation in the study.

2. Adult ≥ 18 years old at the time of informed consent.

3. Stage IIIB/IIIC (not amenable to curative surgery or radiation) or IV NSCLC at the time of study entry.

4. Histologically or cytologically confirmed diagnosis of NSCLC with EGFR mutations known to be associated with EGFR TKI sensitivity, T790M negative, and MET gene amplification defined as Gene Copy Number (GCN) ≥ 5 per central Novartis laboratory

5. Mandatory provision of a formalin-fixed, paraffin embedded tumor tissue sample (a newly obtained tumor sample, or archival tumor block/slides taken after progression on prior line of EGFR TKI.

6. Participants must have failed maximum one prior line of therapy (either to 1st/2nd generation EGFR TKIs or osimertinib) for advanced/metastatic disease and must be candidates for platinum (cisplatin or carboplatin) - pemetrexed doublet based chemotherapy.

7. At least one measurable lesion as defined by RECIST 1.1.

8. ECOG performance status (PS) of 0 or 1.

1. Formulaire de consentement éclairé signé obtenu avant la participation à l’étude.
2. Adulte ≥ 18 ans au moment de la signature du consentement éclairé.
3. CBNPC stade IIIB/IIIC (non éligible à la chirurgie curative ou à la radiothérapie) ou IV au moment de l'inclusion dans l'étude.
5. Un diagnostic de CBNPC histologiquement ou cytologiquement confirmé avec EGFR mutations associé a ITK EGFR sensibilité, T790M négatif et amplification du gène MET définie comme nombre de copies du gène (GCN) ≥ 5 déterminé par le laboratoire centralisé Novartis.
7. Les patients doivent être en échec au maximum d'une ligne de traitement antérieure (soit ITK EGFR de 1ère/2ème génération soit osimertinib) pour une maladie avancée/métastatique (CBNPC stade IIIB/IIIC [non éligible à la chimioradiothérapie définitive] ou stade IV) et doivent être candidats à la chimiothérapie à base de platine (cisplatine ou carboplatine)-pemetrexed.

E.4

Principal exclusion criteria

1. Prior treatment with any MET inhibitor or HGF-targeting therapy.

2. Participants with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms

3. 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)

4. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome

5. Treatment with a prior 1st or 2nd generation EGFR TKIs (e.g. erlotinib, gefitinib, afatinib, dacomitinib) or osimertinib within 14 days or approximately 5x half-life, whichever is shorter, of the first dose of study treatment

6. Unable or unwilling to swallow tablets as per dosing schedule

1. Traitement antérieur par tout inhibiteur de MET ou thérapie ciblant le ligand de MET (HGF).

2. Présence de métastases cérébrales symptomatiques chez des patients neurologiquement instables ou ayant nécessité des doses croissantes de corticoïdes au cours des 2 semaines précédant l'inclusion dans l'étude pour la prise en charge des symptômes neurologiques.
3. Présence ou antécédents de maladie pulmonaire interstitielle ou de pneumopathie interstitielle, y compris pneumopathie radique cliniquement significative (c'est-à-dire ayant une incidence sur les activités de la vie quotidienne ou nécessitant une intervention thérapeutique).
4. Syndrome du QT long, antécédents familiaux de mort subite idiopathique ou du syndrome du QT long congénital.
5. Traitement antérieur par un ITK EGFR de 1ère ou 2ème génération (par ex. erlotinib, géfitinib, afatinib, dacomitinib) ou osimertinib dans les 14 jours ou environ 5 demi-vies, (la durée la plus courte prévalant) précédant la première dose du traitement à l'étude.
6. Patient incapable d’avaler ou ne voulant pas avaler les comprimés conformément au schéma posologique.

E.5 End points

E.5.1

Primary end point(s)

Run-in: Incidence of Dose Limiting Toxicities (DLT) during cycle 1
Randomized part: Progression-free survival (PFS) by BIRC as per RECIST 1.1

Partie Run-in: l'incidence de la toxicité dose-limitante (TDL) au cours du cycle 1.
Partie Randomisé: la survie sans progression (SSP) selon l’avis du BIRC conformément aux critères RECIST 1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

The interim analysis (IA) for futility is planned for PFS in this study when approximately 65 events have occurred (40% of total PFS events) at approximately 18.5 months from the date of first participant randomized in the randomized part of the study. A final analysis will be performed at the end of the study.

L'analyse intermédiaire (IA) de la futilité pour la survie sans progression (SSP) est prévue lorsque environ 65 événements se seront produits (40% du total des événements de SSP) après environ 18,5 mois à compter de la date du premier patient inclus dans la partie randomisée de l'étude. Une analyse finale sera effectuée à la fin de l'étude.

E.5.2

Secondary end point(s)

Run-in Part:
• Safety: Incidence, type, and severity of adverse events per Common Terminology Criteria for Adverse Events (CTCAE) version 5.00 including changes in laboratory values, vital signs, liver assessments and cardiac assessments; Tolerability: dose interruptions, reductions, dose intensity, and duration of exposure for all drug components
• Plasma PK concentrations and derived PK parameters
• All calculated per RECIST 1.1 by investigator: Overall response rate (ORR), Duration of response (DOR), Time to response (TTR), Disease control rate (DCR), Progression free survival (PFS)

Randomized part:
All calculated per RECIST 1.1, both by BIRC and investigator:
• Overall response rate (ORR)
• Overall intracranial response rate (OIRR)
• Duration of response (DOR)
• Time to response (TTR)
• Disease control rate (DCR)

All calculated by investigator:
• PFS2 (PFS after next-line of treatment)

The association between MET amplification status as measured in ctDNA at baseline with PFS and ORR by BIRC using RECIST 1.1 criteria

Characterize the pharmacokinetics of capmatinib, osimertinib, and osimertinib's active metabolites (AZ5104 and AZ7550) by assessing plasma PK concentrations

Overall Survival

Safety profile of capmatinib in combination with osimertinib

Change from baseline in European Organization for Research and Treatment of Cancer (EORTC) QLQ-LC13, QLQ-C30, EuroQoL-5 Dimension-5 Level/EQ-5D-5L, and NCCN Fact Brain Symptoms Index questionnaires

Intracranial anti-tumor activity in participants with Central Nervous System (CNS) lesions at baseline (e.g. Duration of intracranial response (DOIR), time to intracranial response (TTIR) and intracranial disease control rate (IDCR), all by BIRC as per RANO-BM criteria).

Partie Run-in
- Le profil de tolérance et l’innocuité de l’association capmatinib-osimertinib, en évaluant l’incidence, le type et la sévérité des événement indésirables (EIs) selon le CTCAE 5.0, ainsi que les interruption, réduction et l’intensité de la dose.
- Concentrations plasmatiques et paramètres PK dérivés
- Evaluer la réponse tumorale de l’association capmatinib-osimertinib selon le critères RECIST 1.1 évalués par l’investigateur (taux de réponse global (ORR), durée de réponse (DOR), temps de réponse (TTR), taux de control de la maladie (DCR), survie sans progression (PFS))

Partie randomisée
- Tous calculés selon les critères RECIST 1.1 par le BIRC et l'investigateur:
• taux de réponse global (ORR)
• taux de réponse global intracrânienne (OIRR),
•durée de réponse (DOR)
•temps de réponse (TTR)
•taux de control de la maladie (DCR)
- Tous calculés par l'investigateur:
• SSP2 (SSP sous la 2ème ligne de traitement)
- Caractériser le profil pharmacocinétique de capmatinib, d’osimertinib et des métabolites actifs d’osimertinib (AZ5104 et AZ7550) de l’association capmatinib-osimertinib.
- Evaluer la survie globale (SG)
- Le profil de tolérance de l’association capmatinib-osimertinib comparativement au traitement platine-pemetrexed
- Evaluer si l’association capmatinib-osimertinib améliore la qualité de vie liés des patients par rapport à la chimiothérapie.
- Evaluer l'activité antitumorale intracrânienne de l’association capmatinib-osimertinib chez des patients présentant des localisations cérébrales à la baseline (durée de réponse intracrânienne, temps de réponse intracrânienne, taux de control de la maladie intracrânienne, évaluées selon le critères RANO-BM lors de la BIRC).

E.5.2.1

Timepoint(s) of evaluation of this end point

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

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

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

Tolérabilité

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

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)

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

Yes

E.8.4

The trial involves multiple sites in the 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

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

Chile

China

Colombia

Hong Kong

India

Israel

Japan

Korea, Republic of

Malaysia

Mexico

Russian Federation

Serbia

Singapore

Taiwan

Thailand

United States

Vietnam

Bulgaria

Croatia

France

Germany

Hungary

Italy

Lithuania

Netherlands

Poland

Portugal

Romania

Slovenia

Spain

United Kingdom

Argentina

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

LVLS

La Dernière visite du dernier patient

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

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:

147

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

245

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)

There are currently no specific plans.

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

2021-06-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-09-10

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

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Orphan Designation Number:
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