Clinical Trials Register

Summary
EudraCT Number:	2017-000076-28
Sponsor's Protocol Code Number:	BO29554
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-06-17
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2017-000076-28

A.3

Full title of the trial

A PHASE II/III MULTICENTER STUDY EVALUATING THE EFFICACY AND SAFETY OF MULTIPLE TARGETED THERAPIES AS TREATMENTS FOR PATIENTS WITH ADVANCED OR METASTATIC NON SMALL CELL LUNG CANCER (NSCLC) HARBORING ACTIONABLE SOMATIC MUTATIONS DETECTED IN BLOOD (B-FAST: BLOOD-FIRST ASSAY SCREENING TRIAL)

STUDIO MULTICENTRICO DI FASE II/III VOLTO A VALUTARE L¿EFFICACIA E LA SICUREZZA DI MOLTEPLICI TERAPIE A BERSAGLIO MOLECOLARE COME TRATTAMENTI PER PAZIENTI AFFETTI DA CARCINOMA POLMONARE NON A PICCOLE CELLULE (NSCLC) AVANZATO O METASTATICO CHE PRESENTINO MUTAZIONI SOMATICHE TARGET RILEVATE NEL SANGUE (BFAST: BLOOD-FIRST ASSAY SCREENING TRIAL)

A.3.1

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

A Study Evaluating the Efficacy and Safety of Multiple Targeted Therapies as Treatments for Patients with Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) Harboring Actionable Somatic Mutations Detected in Blood (B-FAST: blood-first assay screening trial)

Studio per valutare l'efficacia e la
sicurezza di molteplici terapie a bersaglio molecolare come trattamenti per pazienti affetti da carcinoma polmonare non a piccole
cellule (NSCLC) avanzato o metastatico che presentino mutazioni somatiche target rilevate nel sangue ( (B-FAST: blood-first assay
screening trial)

A.3.2

Name or abbreviated title of the trial where available

A Study Evaluating the Efficacy and Safety of Multiple Targeted Therapies as Treatments for Patients

Studio per valutare l'efficacia e la sicurezza di molteplici terapie a bersaglio molecolare come tra

A.4.1

Sponsor's protocol code number

BO29554

A.5.4

Other Identifiers

Name:

B-FAST

Number:

B-FAST

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	F. HOFFMANN - LA ROCHE LTD.
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	F. Hoffmann-La Roche Ltd
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	F. Hoffmann-La Roche Ltd.
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	0000000
B.5.5	Fax number	000000
B.5.6	E-mail	global.rochegenentechtrials@roche.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	Alectinib
D.3.2	Product code	RO5424802/F03
D.3.4	Pharmaceutical form	Capsule, hard
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	ALECTINIB
D.3.9.2	Current sponsor code	Ro542-4802/F03, Ro542-4802/F16
D.3.9.3	Other descriptive name	ALK INHIBITOR
D.3.9.4	EV Substance Code	SUB178557
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	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	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	Atezolizumab (MPDL3280A)
D.3.2	Product code	RO5541267
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	ATEZOLIZUMAB
D.3.9.2	Current sponsor code	RO5541267
D.3.9.4	EV Substance Code	SUB178312
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	60
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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 500 mg powder for concentrate for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Ely Lilly Netherlands
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.2	Product code	[na]
D.3.4	Pharmaceutical form	Powder 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 DISODICO
D.3.9.1	CAS number	137281-23-3
D.3.9.2	Current sponsor code	-
D.3.9.4	EV Substance Code	SUB09655MIG
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	500
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	Gemcitabine Actavis 38 mg/ml powder for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Actavis Group - Iceland
D.2.1.2	Country which granted the Marketing Authorisation	Malta
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	Gemcitabine
D.3.2	Product code	[na]
D.3.4	Pharmaceutical form	Lyophilisate 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	GEMCITABINA
D.3.9.1	CAS number	95058-81-4
D.3.9.2	Current sponsor code	-
D.3.9.4	EV Substance Code	SUB07892MIG
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	1000
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	Cisplatin NeoCorp 1 mg/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	Hexal AG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.2	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	CISPLATINO
D.3.9.2	Current sponsor code	-
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: 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.2.1.1.1	Trade name	Carboplatin-Teva 10 mg/ml Concentrate for Solution for Infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Pharma B.V. - Netherlands
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
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.3.2	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	-
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.IMP: 7
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	Gitrabin 38 mg/mL powder for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Actavis Group PTC - Iceland
D.2.1.2	Country which granted the Marketing Authorisation	Romania
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	Gemcitabine
D.3.2	Product code	[na]
D.3.4	Pharmaceutical form	Lyophilisate 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	GEMCITABINA
D.3.9.1	CAS number	95058-81-4
D.3.9.2	Current sponsor code	-
D.3.9.4	EV Substance Code	SUB07892MIG
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	1000
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: 8
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	CARBOPLATINE TEVA 10 mg/mL
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Sante - Paris
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	Carboplatin
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	-
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.IMP: 9
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	Carboplatin-GRY 10 mg / ml
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva GmbH,
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.2	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	-
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.IMP: 10
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	TECENTRIQ
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE REGISTRATION LIMITED
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	na
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	ATEZOLIZUMAB
D.3.9.2	Current sponsor code	RO5541267
D.3.9.4	EV Substance Code	SUB178312
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	60
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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: 11
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.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	na
D.3.2	Product code	[na]
D.3.4	Pharmaceutical form	Capsule, hard
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	ENTRECTINIB
D.3.9.1	CAS number	1108743-60-7
D.3.9.2	Current sponsor code	RO7102122
D.3.9.4	EV Substance Code	SUB177830
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	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: 12
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	Zelboraf
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH - EMEA/H/C/002409
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Zelboraf
D.3.2	Product code	[RO5185426]
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	VEMURAFENIB
D.3.9.1	CAS number	918504-65-1
D.3.9.2	Current sponsor code	RO5185426
D.3.9.4	EV Substance Code	SUB32161
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	240
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: 13
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	Cotellic
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH - EMEA/H/C/003960
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Cotellic
D.3.2	Product code	[RO5514041]
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	Cobimetinib (GDC-0973)
D.3.9.1	CAS number	934660-93-2
D.3.9.2	Current sponsor code	RO5514041
D.3.9.4	EV Substance Code	SUB122319
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.3.11 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

Advanced or metastatic Non-small cell lung cancer (NSCLC)

Carcinoma polmonare non a piccole cellule (NSCLC) avanzato o metastatico

E.1.1.1

Medical condition in easily understood language

Advanced or metastatic NSCLC is lung cancer that has spread to areas near the lungs or other organs

Il carcinoma polmonare non a piccole cellule (NSCLC) avanzato o metastatico ¿ un cancro ai polmoni che si ¿ diffuso alle aree vicine ai polmoni o ad altri organi

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	10029521
E.1.2	Term	Non-small cell lung cancer stage IIIB
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

• To evaluate the efficacy of multiple therapies in patients with NSCLC selected according to results from the FoundationOne Liquid Companion Diagnostic (F1LCDx): alectinib (ALK+; RET+); entrectinib (ROS1+);
atezolizumab (atezo) + cobimetinib (cobi) + vemurafenib (vem) (BRAF V600+)
• To evaluate the efficacy of atezo compared with platinum-based chemotherapy in treatment-naive patients with inoperable Stage IIIB or Stage IV NSCLC in patients who are blood tumor mutational burden positive according to F1LCDx (Cohort C)

- Valutare l’efficacia di molteplici terapie in pazienti affetti da carcinoma polmonare non a piccole cellule (NSCLC) in accordo ai risultati ottenuti da FoundationOne Liquid Companion Diagnostic (F1LCDx): alectinib (ALK+; RET+); entrectinib (ROS1+); atezolizumab (atezo) + cobimetinib (cobi) + vemurafenib (vem) (BRAF
V600+)
- Valutare l’efficacia di atezolizumab rispetto a chemioterapia a base di platino in pazienti naïve alla chemioterapia affetti da NSCLC inoperabile in stadio IIIB o stadio IV positivi al test F1LCDX (Coorte C)

E.2.2

Secondary objectives of the trial

• To evaluate the safety and tolerability of alectinib, atezo, entrectinib, atezo + cobi + vem (Cohorts A, B, C, D, E)
• To explore the pharmacokinetic (PK) characteristics of alectinib in RET+ patients (Cohort B), entrectinib in ROS1+ patients (Cohort D), atezo in BRAF V600+ patients (Cohort E)
• To evaluate the impact of study treatment on patient-reported outcome (PROs)
• To evaluate the efficacy of entrectinib in patients with ROS1+ advanced or metastatic NSCLC and atezo +cobi + vem in patients with BRAF V600+, as determined by the F1LCDx assay
• To assess prognostic effect and pharmacodynamics of exploratory biomarkers in blood, and their association with disease status, mechanisms of resistance, and/or response to alectinib (Cohorts A, B), atezo (Cohort C), entrectinib (Cohort D)

- Valutare la sicurezza e la tollerabilità di alectinib, atezolizumab, entrectinib, atezo+cobi+vem (Coorti A, B, C, D,E)
- Indagare le caratteristiche farmacocinetiche di alectinib in pazienti RET+ (Coorte B), di entrectinib in pazienti ROS1+ (Coorte D), di atezo in pazienti BRAF V600+ (Coorte E)
- Valutare l'impatto dei trattamenti sui PRO (outcome riferiti dai pazienti)
- Valutare l’efficacia di entrectinib in pazienti affetti da NSCLC ROS1+ e atezo+cobi+vem in pazienticon BRAF V600+, in base a quanto stabilito dal test F1LCDx
- Valutare l’effetto prognostico e la farmacodinamica dei biomarcatori esplorativi nel sangue, nonché la loro associazione con lo stato di malattia, i meccanismi di resistenza e/o la risposta a: alectinib (Coorte A, B), atezo (Coorte C), entrectinib (Coorte D)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Histologically or cytologically confirmed diagnosis of unresectable Stage IIIb not amenable to treatment with combined modality chemoradiation (advanced) or Stage IV (metastatic) NSCLC
- Age >=18 years
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
- Measurable disease (as defined by RECIST, v1.1)
- Adequate recovery from most recent systemic or local treatment for cancer
- Adequate organ function
- Life expectancy >=12 weeks
- For female patients of childbearing potential and male patients, willingness to use acceptable methods of contraception

- Diagnosi di NSCLC in stadio IIIb non candidabile a trattamento con chemioradioterapia in modalità combinata (avanzato) o in stadio IV (metastatico), confermata mediante esame istologico o citologico.
- Età >= 18 anni
- Performance status secondo l’Eastern Cooperative Oncology Group (ECOG) pari a 0-2
- Malattia misurabile (secondo i criteri RECIST v1.1)
- Recupero adeguato dal trattamento antitumorale sistemico o locale più recente
- Adeguata funzionalità d’organo
- Aspettativa di vita >= 12 settimane
- Per le donne in età fertile e gli uomini, disponibilità a utilizzare metodi contraccettivi accettabili

E.4

Principal exclusion criteria

- Inability to swallow oral medication
- Women who are pregnant or lactating
- Symptomatic, untreated CNS metastases Patients with treated and/or asymptomatic brain metastases may still be eligible for
treatment on the study depending on individual cohort
requirements; see the cohort specific appendices for details regarding eligibility
- History of malignancy other than NSCLC within 5 years prior to screening, with the exception of malignancies with a negligible
risk of metastasis or death (e.g., 5 year OS rate >= 90%), such as adequately treated carcinoma in situ of the cervix, non melanoma
skin carcinoma, localized prostate cancer, ductal carcinoma in situ of breast, or Stage I uterine cancer
-Significant cardiovascular disease
-Known HIV positivity or AIDS-related illness
-Either a concurrent condition or history of a prior condition that places the patient at unacceptable risk if he/she were treated with
the study drug or confounds the ability to interpret data from the study
-Inability to comply with other requirements of the protocol

- Incapacità di ingerire i medicinali per via orale
- Donne in gravidanza o allattamento
- Metastasi sintomatiche non trattate a carico del sistema nervoso centrale (SNC). I pazienti con metastasi cerebrali trattate e/o
asintomatiche potranno essere comunque ritenuti idonei al trattamento nello studio in base ai requisiti delle singole coorti; per
maggiori dettagli sull’idoneità, consultare le appendici specifiche delle coorti.
- Anamnesi positiva per neoplasia maligna diversa dall’NSCLC nei 5 anni precedenti allo screening, fatta eccezione per quelle
soggette a un rischio trascurabile di metastasi o decesso (per es. tasso di OS a 5 anni >= 90%), quali forme adeguatamente trattate
di carcinoma in situ della cervice, carcinoma cutaneo non melanomatoso, carcinoma localizzato della prostata, carcinoma duttale
in situ della mammella o carcinoma uterino in stadio I.
- Cardiovasculopatia significativa
- Positività nota al virus dell’immunodeficienza umana (HIV) o malattia correlata a sindrome da immunodeficienza acquisita (AIDS)
- Condizione concomitante o anamnesi positiva per condizioni pregresse che esporrebbero il paziente a un rischio inaccettabile
qualora venisse trattato con il farmaco in studio o che comprometterebbero la capacità di interpretare i dati della ricerca
- Incapacità di rispettare altri requisiti del protocollo

E.5 End points

E.5.1

Primary end point(s)

1. Investigator-assessed ORR based on confirmed objective response (Cohorts A, B and D)
2. Investigator-assessed PFS according to RECIST v1.1 (Cohort C) in bTMB the primary population of patients with a bTMB level equal to or greater than the higher validated cutoff (PP1)
3. Investigator-assessed 12-month time in response (TIR) per RECIST v1.1 (Cohort E)

1. ORR valutato dallo sperimentatore in base alla risposta obiettiva confermata (Coorti A, B e D)
2. Valutazione della PFS da parte del medico secondo i criteri RECIST v1.1 (Coorte C) in bTMB la popolazione primaria di pazienti con un livello di bTMB uguale o maggiore rispetto cutoff più alto validato (PP1)
3. TIR a 12 mesi valutato dallo sperimentatore secondo i criteri RECIST v1.1 (Coorte E)

E.5.1.1

Timepoint(s) of evaluation of this end point

1-3. Up to 6 years

1-3. Fino a 6 anni

E.5.2

Secondary end point(s)

1. Investigator-assessed DOR, CBR, and PFS per RECIST v1.1 (Cohorts A, B and D)
2. IRF-assessed ORR, DOR, CBR, and PFS per RECIST v1.1 (Cohorts A and B)
3. IRF-assessed PFS, ORR, and DOR according to RECIST v1.1 (Cohort C)
4. Investigator-assessed ORR, and DOR according to RECIST v1.1 (Cohort C)
5. Investigator- and IRF-assessed time to CNS progression according to RECIST v1.1 (Cohort D)
6. Investigator-assessed intracranial tumor response rate by RECIST 1.1 in patients with measurable CNS disease at baseline (Cohort D)
7. OS (Cohorts A, B, D and E)
8. Investigator-assessed PFS rates at 6-month and 1-year landmark timepoints (Cohort C)
9. Incidence, type, and severity of adverse events (based on the NCI CTCAE v4.0), including SAEs and AEs of special interest (Cohorts A, B, C and D)
10. Changes in vital signs, physical findings, and clinical laboratory results during and following administration of protocol-specified IMPs (Cohorts A, B and D)
11. DLTs, if any, associated with alectinib at escalating doses in RET+ patients (Cohort B)
12. PK parameters of alectinib in RET+ patients (Cohort B)
13. Population PK analysis for entrectinib (Cohort D)
14. Proportion of patients who improved compared with baseline in patient-reported lung cancer symptoms of cough, dyspnea, and chest pain and TTD as measured by SILC (Cohorts A, B, C, D and E)
15. Proportion of patients presenting with measurable CNS disease at baseline who improve compared with baseline in patient-reported cognitive function, fatigue, health-related quality of life (HRQoL), headache, and vision disorder per the corresponding scales of the EORTC QLQ-C30 and BN20 (Cohort D)
16. Mean change from baseline in HRQoL, patient functioning, and symptoms as measured by the EORTC
QLQ-C30 (Cohorts A, B, C, D and E)
17. Health status as assessed by the EQ-5D-5L questionnaire (Cohorts A, B, C, D and E)
18. Relationship between circulating biomarkers related to alectinib exposure and efficacy (Cohorts A and B), to atezolizumab efficacy (Cohort C) to entrectinib efficacy (Cohort D), and atezo + cobi + vem efficacy (Cohort E)
19. OS in bTMB PP1 (Cohort C)
20. Investigator-assessed PFS according to RECIST v1.1 in bTMB the secondary population of all patients who are bTMB-positive, which is the intent-to-treat (ITT) population in this cohort (PP2) [Cohort C]
21. OS in bTMB PP2 (Cohort C)
22. Investigator and IRF-assessed -assessed ORR, DOR, and PFS per RECIST v1.1 (Cohort E)
23. 9-month TIR (Cohort E)
24. 12-month TIR (Cohort E)
25. Serum concentration of atezo at specified timepoints (Cohort E)
26. Presence of ADAs against atezo during the study relative to the presence of ADAs at baseline (Cohort E)

1. DOR, CBR e PFS valutati dallo sperimentatore secondo i criteri RECIST v1.1 (Coorti A, B e D)
2. ORR, DOR, CBR e PFS valutati dall'IRF secondo i criteri RECIST v1.1 (Coorti A e B)
3. PFS, ORR e DOR valutati dall¿IRF secondo i criteri RECIST v1.1 (Coorte C)
4. ORR e DOR valutati dallo sperimentatore secondo i criteri RECIST v1.1 (Coorte C)
5. Tempo alla progressione SNC valutato dallo sperimentatore e dall’IRF secondo i criteri RECIST v1.1 (Coorte D)
6. Tasso di risposta tumorale intracranica valutato dallo sperimentatore secondo i criteri RECIST v1.1 in pazienti con malattia dell’SNC misurabile al basale (Coorte D)
7. OS (Coorti A, B, D, e E)
8. Tassi di PFS valutati dallo sperimentatore agli intervalli di riferimento a 6 mesi e 1 anno (Coorte C)
9. Incidenza, tipologia e severità degli eventi avversi (secondo i criteri NCI CTCAE v4.0), ivi compresi SAE ed eventi avversi di interesse particolare (Coorti A, B, C e D)
10. Variazioni di segni vitali, obiettività e risultati clinici di laboratorio durante e dopo la somministrazione degli IMP specificati dal protocollo (Coorti A, B e D)
11. Eventuali DLT associate ad alectinib a dosi incrementali progressive (Coorte B)
12. Parametri farmacocinetici di alectinib nei pazienti RET (Coorte B)
13. Analisi farmacocinetica di popolazione su entrectinib (Coorte D)
14. Percentuale di soggetti che registrano un miglioramento rispetto al basale nei seguenti sintomi del carcinoma polmonare riferiti dai pazienti valutati secondo la scala SILC: tosse, dispnea e dolore toracico e TTD (Coorti A, B,C, D e E)
15. Percentuale di soggetti con malattia dell’SNC misurabile al basale che registrano un miglioramento rispetto al basale nella funzione cognitiva, nell’affaticamento, nella HRQoL, nel mal di testa e nei problemi alla vista riferiti dai pazienti secondo le scale corrispondenti dei questionari QLQ-C30 e BN20 dell’EORTC (Coorte D)
16. Variazione media rispetto al basale di HRQoL, capacità dei pazienti di svolgere attività e sintomi, valutati secondo il questionario QLQ-C30 dell’EORTC (Coorti A, B, C, D e E)
17. Condizioni di salute valutate secondo il questionario EQ-5D-5L (Coorti A, B, C, D e E)
18. Correlazione tra i biomarcatori circolanti connessi all'esposizione e all'efficacia di alectinib (Coorti A e B), all’efficacia di atezo (Coorte C), all'efficacia di entrectinib (Coorte D), all’efficacia di atezo+cobi+vem (Coorte E)
19. OS in bTMB PP1 (Coorte C)
20. Valutazione della PFS da parte del medico secondo i criteri RECIST v1.1 in bTMB PP2 (Coorte C)
21. OS in bTMB PP2 (Coorte C)
22. ORR valutato dall’IRF, DOR e PFS secondo i criteri RECIST v1.1 (Coorte E)
23. TIR a 9 mesi (Coorte E)
24. TIR a 12 mesi (Coorte E)
25. Concentrazione sierica di atezolizumab a specifici timepoint (Coorte E)
26. Presenza di ADA diretti contro atezolizumab durante lo studio rispetto alla presenza di ADA al basale (Coorte E)

E.5.2.1

Timepoint(s) of evaluation of this end point

1-7. Up to 6 years
8. At 6 month and 1 year
9-10. Up to 6 years
11. From Day 1 (D1) to D28 of Cycle 1 (C1)
12. Dose-Finding Phase: C1D1, C1D8, C2D1, C3D1, C4D1
Expansion Phase: C1D1, C2D1, C3D1, C4D1
13. C1D1, C2D1, C3D1, C4D1, C5D1 and all subsequent D1 of each treatment cycle until the end of treatment
14- 17. At 3 and 6 months following disease progression up to 6 years
18-22. Up to 6 years
23. 9 months
24. 12 months
25-26. C1D1, C2D1, C3D1, C4D1, C8D1, C12D1, C16D1 and at treatment discontinuation visit

1-7. Fino a 6 anni
8. Al mese 6 e ad 1 anno
9-10. Fino a 6 anni
11. Dal Giorno 1 (D1) al Giorno 28 del Ciclo 1 (C1)
12. Fase di determinazione della dose: C1D1, C1D8, C2D1, C3D1, C4D1
Fase con espansione della dose: C1D1, C2D1, C3D1, C4D1
13. C1D1, C2D1, C3D1, C4D1, C5D1 e e tutti i successivi D1 di ciascun ciclo di trattamento fino alla fine del trattamento
14- 17. Al mese 3 e 6 siccessivi la progression di malattia fino a 6 anni
18-22. Fino a 6 anni
23. Mese 9
24. Mese 12
25-26. C1D1, C2D1, C3D1, C4D1, C8D1, C12D1, C16D1 e 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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

Biomarkers

Biomarcatori

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)

Yes

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

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

Australia

Brazil

Canada

Chile

Costa Rica

Hong Kong

Israel

Korea, Republic of

Mexico

New Zealand

Peru

Russian Federation

Serbia

Singapore

Taiwan

Thailand

Turkey

United States

Belgium

France

Germany

Italy

Poland

Spain

Argentina

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

The end of this study is defined as the date when the last patient, last visit (LPLV) or assessment occurs for the collection of the last data point for the last treatment cohort.

The umbrella nature of this protocol may provide for an extension of
the overall duration of this study to meet the objectives of additional cohorts and/or additional therapies added through protocol amendments

La fine dello studio coincide con la data in cui ha luogo l’ultima visita dell’ultimo paziente (LPLV) o la valutazione per la raccolta dell’ultima osservazione nell’ultima coorte di trattamento. Le singole coorti potranno concludersi prima della fine dello studio una volta interamente completati il trattamento, il follow-up e la raccolta dei dati predefiniti.

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:

284

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

284

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

300

F.4.2.2

In the whole clinical trial

660

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)

Currently, the Sponsor does not have any plans to provide study
treatments or interventions to patients who have completed the study.
The Sponsor may evaluate the appropriateness of continuing to provide
the drugs used during the study after evaluation of the primary and
secondary efficacy outcome measures and safety data gathered in the
study and in accordance with the Roche Global Policy on Continued
Access to IMP:
http://www.roche.com/policy_continued_access_to_investigational_
medicines.pdf

Attualmente,lo Sponsor non prevede di fornire i tratt o interventi in studio dopo che i paz che hanno completato lo studio.Lo Sponsor potrebbe valutare se continuare a fornire i farmaci utilizzati dopo la valutazione prim e sec dei dati di efficacia e di sicurezza raccolti e in accordo alla Policy internaz di Roche sull'accesso continuato ai medicinali in sperimentazione, disponibile al seguente sito web:http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-09-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-07-19

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

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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