Clinical Trials Register

Summary
EudraCT Number:	2020-000100-11
Sponsor's Protocol Code Number:	GO41892
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:	2021-01-21
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

2020-000100-11

A.3

Full title of the trial

A PHASE III, MULTICENTER, RANDOMIZED, OPEN-LABEL, CONTROLLED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND PHARMACOKINETICS OF TEZOLIZUMAB GIVEN IN COMBINATION WITH CABOZANTINIB VERSUS DOCETAXEL MONOTHERAPY IN PATIENTS WITH METASTATIC NON-SMALL CELL LUNG CANCER PREVIOUSLY TREATED WITH AN ANTI-PD-L1/PD-1 ANTIBODY AND PLATINUM-CONTAINING CHEMOTHERAPY

STUDIO DI FASE III, MULTICENTRICO, RANDOMIZZATO, IN APERTO E CONTROLLATO VOLTO A VALUTARE L’EFFICACIA, LA SICUREZZA E LA FARMACOCINETICA DI ATEZOLIZUMAB SOMMINISTRATO IN ASSOCIAZIONE A CABOZANTINIB IN CONFRONTO A DOCETAXEL IN MONOTERAPIA IN PAZIENTI CON CARCINOMA POLMONARE NON A PICCOLE CELLULE, METASTATICO, PRETRATTATO CON UN ANTICORPO ANTI-PD-L1/PD-1 E CHEMIOTERAPIA A BASE DI PLATINO

A.3.1

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

Study of Atezolizumab in Combination with Cabozantinib Versus Docetaxel in Patients with Metastatic Non-Small Cell Lung Cancer Previously Treated With an Anti-PD-L1/PD-1 Antibody and Platinum-Containing Chemotherapy

Studio con Atezolizumab in associazione con Cabozantinib in confronto a Docetaxel in monoterapia pazienti con carcinoma in pazienti affetti da carcinoma polmonare non a piccole cellule, metastatico, pretrattato con anticorpo anti-PD-L1/PD-1 e chemioterapia a base di platino.

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

GO41892

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. Hoffman-La Roche Ltd.
B.4.2	Country	Switzerland
B.4.1	Name of organisation providing support	Exelisis Inc.
B.4.2	Country	United States
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	4047
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	000000
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	Yes
D.2.1.1.1	Trade name	Tecentriq
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH - AIC EU/1/17/1220/001
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	Atezolizumab
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.3.9.3	Other descriptive name	TECENTRIQ
D.3.9.4	EV Substance Code	SUB190577
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: 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	Cabozantinib
D.3.2	Product code	[RO7047650]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Cabozantinib
D.3.9.2	Current sponsor code	RO7047650
D.3.9.3	Other descriptive name	Cabozantinib S-malate
D.3.9.4	EV Substance Code	SUB176318
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.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	Docetaxel Accord 80 mg/4 ml concentrate for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Accord Healthcare S.L.U. - AIC EU/1/12/769/002
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	Docetaxel
D.3.2	Product code	[-]
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	DOCETAXEL
D.3.9.2	Current sponsor code	RO0647746
D.3.9.4	EV Substance Code	SUB12492MIG
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	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.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	Docetaxel AqVida 20 mg/ml concentrate for solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	AqVida GmbH - AIC 92726.00.00
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	Docetaxel
D.3.2	Product code	[-]
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	DOCETAXEL
D.3.9.2	Current sponsor code	RO0647746
D.3.9.4	EV Substance Code	SUB12492MIG
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	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

Non-small cell lung cancer (NSCLC)

Carcinoma polmonare non a piccole cellule (NSCLC)

E.1.1.1

Medical condition in easily understood language

NSCLC is a type of lung cancer.

NSCLC è un tipo di carcinoma polmonare

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10029522
E.1.2	Term	Non-small cell lung cancer stage IV
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 atezolizumab in combination with cabozantinib compared with docetaxel monotherapy in patients with metastatic NSCLC who were previously treated with an anti- anti-Programmed death-ligand 1 (PD-L1)/PD-1 antibody and platinum-containing chemotherapy

Valutare l’efficacia di atezolizumab somministrato in associazione a cabozantinib in confronto a docetaxel in monoterapia in pazienti affetti da carcinoma polmonare non a piccole cellule (NSCLC) pretrattati con un anticorpo ANTI - PD-L1/PD-1 e chemioterapia a base di platino

E.2.2

Secondary objectives of the trial

-To evaluate the safety of atezolizumab and cabozantinib compared with docetaxel monotherapy in this patient population
-To characterize the pharmacokinetic (PK) profile of atezolizumab and cabozantinib
-To evaluate the immune response to atezolizumab and cabozantinib

-Valutare la sicurezza di atezolizumab più cabozantinib in confronto a docetaxel in monoterapia per questa popolazione di pazienti
-Caratterizzare il profilo di PK di atezolizumab e cabozantinib
-Valutare la risposta immunitaria di atezolizumab e cabozantinib

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age >= 18 years
- Histologically or cytologically confirmed metastatic NSCLC
- Documented radiographic disease progression during or following treatment with platinum-containing doublet chemotherapy and anti-PD-L1/PD-1 antibody, administered concurrently or sequentially for metastatic NSCLC
- Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 outside the central nervous system (CNS) as assessed by investigator
- Known PD-L1 status or availability of tumor tissue for central PD-L1 testing
- Eastern Cooperative Oncology Group performance status score of 0 or 1
- Recovery to baseline or Grade <= 1 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 from toxicities related to any prior treatments, unless adverse events are clinically nonsignificant and/or stable on supportive therapy in the opinion of the investigator
- Adequate hematologic and end-organ function
- For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs, for 5 months after the final dose of atezo and/or 4 months after the final dose of cabo
- For men: agreement to remain abstinent or use contraceptive methods, and agreement to refrain from donating sperm for 4 months after the final dose of cabo, or for 6 months after the final dose of docetaxel

-Età >=18 anni
-NSCLC metastatico confermato dall’analisi istologica o citologica.
-Progressione radiografica della malattia documentata durante o dopo trattamento con chemioterapia a base di platino e anticorpo anti-PD-L1/PD-1 somministrato in concomitanza o in sequenza per NSCLC metastatico.
-Presenza di malattia misurabile in base ai criteri RECIST v1.1 al di fuori del sistema nervoso centrale (SNC) secondo quanto valutato dallo sperimentatore.
-Stato di PD-L1 noto o disponibilità di un campione di tessuto tumorale per l’analisi centrale di PD-L1
-Performance status secondo l’ECOG pari a 0 o 1.
-Risoluzione delle tossicità correlate a trattamenti precedenti al grado basale o a un grado ¿ 1 secondo i criteri NCI CTCAE v5.0, tranne nel caso in cui con terapia di supporto gli eventi avversi siano clinicamente non significativi e/o stabili secondo il parere dello sperimentatore.
-Adeguata funzionalità ematologica, epatica e renale
-Nelle donne in età fertile: consenso ad astinenza da rapporti eterosessuali o ad utilizzare metodi contraccettivi e consenso a non donare ovuli per 5 mesi dopo l’ultima dose di atezolizumab e/o 4 mesi dopo l’ultima dose di cabozantinib
-Negli uomini: consenso a praticare astinenza dai rapporti eterosessuali o a far uso di metodi contraccettivi e consenso ad astenersi dalla donazione di sperma per 4 mesi dopo l’ultima dose di cabozantinib o per 6 mesi dopo l’ultima dose di docetaxel

E.4

Principal exclusion criteria

- Prior therapy with the following agents for NSCLC: Cabo, Docetaxel, Combination of an anti-PD-L1/PD-1 antibody concurrently with a vascular endothelial growth factor -targeting tyrosine kinase inhibitor
- Treatment with investigational therapy within 28 days prior to initiation of study treatment
- Documentation of known sensitizing mutation in the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) fusion oncogene
- Symptomatic, untreated, or actively progressing CNS metastases
- History of leptomeningeal disease
- Uncontrolled tumor-related pain, pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures, uncontrolled or symptomatic hypercalcemia
- Any other active malignancy at the time of initiation of study treatment or diagnosis of another malignancy within 3 years prior to initiation of study treatment that requires active treatment, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, incidental prostate cancer, or carcinoma in situ of the prostate, cervix, or breast
- Significant cardiovascular disease within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
- Stroke, transient ischemic attack, myocardial infarction or other symptomatic ischemic events within 6 months of initiation of study treatment
- Active tuberculosis
- Severe infection within 4 weeks prior to initiation of study treatment
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
- Current treatment with anti-viral therapy for HBV
- Ongoing Grade = 2 sensory or motor neuropathy
- Active or history of autoimmune disease or immune deficiency
- Pharmacologically uncompensated, symptomatic hypothyroidism
- Administration of a live, attenuated vaccine within 4 weeks prior to initiation of study
treatment or anticipation of need for such a vaccine during atezolizumab treatment
or within 5 months after the final dose of atezolizumab
- Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives prior to initiation of study treatment
- Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment
- Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
- History of severe hypersensitivity to docetaxel or to other drugs formulated with polysorbate 80
- Concomitant anticoagulation with oral anticoagulants or platelet inhibitors
- Thromboembolic event within 6 months before initiation of study treatment
- History of risk factors for torsades de pointes
- Corrected QT interval corrected through use of Fridericia's formula > 480 ms per ECG within 14 days before initiation of study treatment
- Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg or diastolic BP > 90 mm Hg despite optimal antihypertensive treatment
- Abdominal fistula, bowel obstruction, GI perforation, or intra-abdominal abscess within 6 months before initiation of study treatment
- Known cavitating pulmonary lesion(s) or known endobronchial disease manifestation
- Lesions invading major pulmonary blood vessels
- Clinically significant hematuria, hematemesis, hemoptysis of > 0.5 teaspoon (2.5 mL) of red blood, coagulopathy, or other history of significant bleeding within 3 months before initiation of study treatment
- Serious non-healing wound/ulcer/bone fracture
- Malabsorption syndrome
- Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption are also excluded
- Requirement for hemodialysis or peritoneal dialysis

-Precedente terapia con agenti per l’NSCLC:Cabozantinib;Docetaxel;associazione concomitante di anticorpo anti-PD-L1/PD-1 e TKI diretto contro il recettore del fattore di crescita endoteliale vascolare
-Trattamento con terapia sperimentale nei 28 gg precedenti l’inizio del trattamento
-Documentazione di mutazione di EGFR od oncogene di fusione ALK.
-Metastasi a carico dell’SNC sintomatiche, non trattate o in progressione attiva.
-Anamnesi positiva per malattia leptomeningea.
-Dolore non controllato correlato al tumore, versamento pleurico, versamento pericardico o ascite non controllato/a che necessita di ricorrenti procedure di drenaggio, ipercalcemia non controllata o sintomatica.
-Qualsiasi altra neoplasia maligna attiva al momento dell’inizio del trattamento in studio o diagnosi di altra neoplasia maligna nei 3 anni precedenti l’inizio del trattamento in studio che necessiti di trattamento attivo, eccetto per tumori curabili localmente che siano stati apparentemente curati, come tumore cutaneo baso- o squamocellulare, tumore prostatico incidentale o carcinoma in situ della prostata, della cervice o della mammella.
-Cardiovasculopatia significativa nei 3 mesi precedenti l’inizio del trattamento in studio, aritmia instabile o angina instabile.
-Ictus, attacco ischemico transitorio, infarto del miocardio o altri eventi ischemici sintomatici entro 6 mesi dall’inizio del trattamento
-Tubercolosi attiva
-Infezione severa nelle 4 sett precedenti l’inizio del trattamento
-Trattamento con antibiotici terapeutici orali o per via e.v. nelle 2 sett precedenti l’inizio del trattamento
-Trattamento in corso con una terapia antivirale per l’HBV
-Neuropatia sensoriale o motoria di grado >= 2 in atto.
-Presenza attiva di o anamnesi positiva per malattia autoimmune o immunodeficienza
-Ipotiroidismo sintomatico non compensato farmacologicamente
-Somministrazione di un vaccino vivo attenuato nelle 4 sett precedenti l’inizio del trattamento in studio o necessità prevista di somministrare un tale vaccino durante il trattamento con atezolizumab
-Trattamento con immunostimolanti sistemici nelle 4 sett o nelle 5 emivite di eliminazione del farmaco precedenti l’inizio del trattamento
-Trattamento con immunosoppressori sistemici nelle 2 sett precedenti l’inizio del trattamento in studio o necessità prevista di immunosoppressori sistemici durante il trattamento in studio
-Ipersensibilità nota ai prodotti contenenti cellule ovariche di criceto cinese o a qualsiasi componente della formulazione di atezolizumab
-Anamnesi positiva per ipersensibilità severa a docetaxel o ad altri farmaci formulati con polisorbato 80
-Trattamento anticoagulante concomitante con anticoagulanti orali o inibitori delle piastrine
-Evento tromboembolico nei 6 mesi precedenti l’inizio del trattamento
-Anamnesi positiva per fattori di rischio per torsione di punta
-Intervallo QT corretto secondo formula di Fridericia (QTcF) > 480 ms all’ECG nei 14 gg precedenti l’inizio del trattamento
-Ipertensione non controllata, da intendersi come pressione arteriosa [PA] sistolica >150 mm Hg o PA diastolica >90 mm Hg nonostante un trattamento antipertensivo ottimale
-Fistola addominale, occlusione intestinale, perforazione GI o ascesso intraddominale nei 6 mesi precedenti l’inizio del trattamento
-Lesione/i polmonare/i con cavitazione nota/e o manifestazione di malattia endobronchiale nota
-Lesioni che invadono i grossi vasi polmonari
-Ematuria clinicamente significativa, emametesi, emottisi > 0,5 cucchiaini (2,5 ml) di sangue rosso, coagulopatia o altra anamnesi positiva per sanguinamento significativo nei 3 mesi precedenti l’inizio del trattamento
-Grave ferita/ulcera/frattura ossea che non va incontro a guarigione
-Sindrome da malassorbimento
-Pazienti con rari problemi ereditari di intolleranza al galattosio, deficit di Lapp lattasi o malassorbimento di glucosio-galattosio
-Necessità di emodialisi o dialisi peritoneale

E.5 End points

E.5.1

Primary end point(s)

Duration of Overall Survival (OS)

Durata della sopravvivenza globale (OS)

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to approximately 43 months

Fino a circa 43 mesi

E.5.2

Secondary end point(s)

1. Duration of PFS as determined by Investigator according to RECIST v1.1
2. Confirmed objective response rate (ORR) as determined by Investigator
3. Duration of response for patients with confirmed ORR
4. Time to confirmed deterioration in patient-reported physical functioning and global health status as measured by the corresponding scores from the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30)
5. PFS rate assessed by IRF and Investigator at 6 months and at 1 year
6. OS rates at 1 and 2 years
7. Incidence and severity of adverse events according to NCI CTCAE v5.0
8. Serum concentration of atezolizumab at specified timepoints
9. Plasma concentration of cabozantinib at specified timepoints
10. Prevalence of anti-drug antibodies (ADAs) to atezolizumab at baseline and incidence of ADAs to atezolizumab after treatment

1. Durata della sopravvivenza libera da progressione (PFS) secondo quanto stabilito dallo sperimentatore in base ai criteri di valutazione della risposta nei tumori solidi, versione 1.1 (RECIST v1.1)
2. Tasso di risposta obiettiva (ORR) confermata secondo quanto stabilito dallo sperimentatore
3. Durata della risposta (DOR) nei pazienti con ORR confermata
4. Tempo al peggioramento confermato dell’attività fisica (PF) e delle condizioni generali di salute (GHS) riferite dal paziente in base ai punteggi corrispondenti del Quality of Life-Core 30 della European Organisation for the Research and Treatment of Cancer (EORTC QLQ-C30).
5.Tassi di PFS valutati dallo sperimentatore a 6 mesi e 1 anno
6.Tassi di OS a 1 e 2 anni
7. Incidenza e severità degli eventi avversi con severità stabilita in base ai criteri comuni di terminologia per gli eventi avversi del National Cancer Institute, versione 5.0 (NCI CTCAE v5.0)
8.Concentrazione sierica di atezolizumab a specifici timepoint.
9.Concentrazione plasmatica di cabozantinib a specifici timepoint
10. Prevalenza di anticorpi anti-farmaco (ADA) diretti contro atezolizumab al basale e incidenza di ADA diretti contro atezolizumab dopo il trattamento

E.5.2.1

Timepoint(s) of evaluation of this end point

1-4. Up to approximately 43 months
5. At 6 months and at 1 year, up to approximately 43 months
6. At 1 and 2 years, up to approximately 43 months
7. Up to approximately 43 months
8. Day 1 of Cycle 1-5, Cycle 8, 12, 16, post treatment follow-up (<= 30 days after final dose)
9. Day 1 of Cycle 1-5
10. Day 1 of Cycle 1-4, Cycle 8, 12, 16, post treatment follow-up (<= 30 days after final dose)

1-4. Fino a circa 43 mesi
5. A 6 mesi e a 1 anno, fino a circa 43 mesi
6. A 1 e 2 anni, fino a circa 43 mesi
7. Fino a circa 43 mesi
8. Giorno 1 del ciclo 1-5, ciclo 8, 12, 16, follow-up post trattamento (<= 30 giorni dopo la dose finale)
9. Giorno 1 del ciclo 1-5
10. Giorno 1 del ciclo 1-4, ciclo 8, 12, 16, follow-up post trattamento (<= 30 giorni dopo la dose finale)

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

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

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

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

Japan

Korea, Republic of

Russian Federation

United States

Austria

Belgium

France

Germany

Greece

Italy

Poland

Spain

United Kingdom

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 this study will occur when all of the following criteria have been met:
* The required number of deaths for the final analysis of OS has been observed.
* The last patient, last visit has occurred.

In addition, the Sponsor may decide to terminate the study at any time.

Lo studio si concluderà quando verranno soddisfatti tutti i seguenti criteri:
-Sarà stato osservato il numero di decessi necessario per l’analisi finale della OS.
-Sarà stata effettuata l’ultima visita dell’ultimo paziente.
Il promotore potrà inoltre decidere di interrompere lo studio in qualsiasi momento

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:

175

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

175

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

280

F.4.2.2

In the whole clinical trial

350

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)

The Sponsor will offer continued access to study treatment (atezolizumab and cabozantinib) free of charge to eligible patients in accordance with the Roche Global Policy

Lo sponsor offrirà un accesso continuo al trattamento di studio (atezolizumab e cabozantinib) gratuitamente per i pazienti eleggibili in conformità con la politica globale di Roche

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	US Oncology
G.4.3.4	Network Country	United States
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Kaiser Permanente, SOCAL
G.4.3.4	Network Country	United States

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-09-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-08-04

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

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Orphan Designation Number:
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