Clinical Trials Register

Summary
EudraCT Number:	2021-000336-55
Sponsor's Protocol Code Number:	D5086C00001
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:	2021-10-18
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

2021-000336-55

A.3

Full title of the trial

A Phase III, Open Label, Randomised, 3 Arm, Multi Centre Study of Savolitinib plus Durvalumab versus Sunitinib and Durvalumab Monotherapy in Participants with MET Driven, Unresectable and Locally Advanced or Metastatic Papillary Renal Cell Carcinoma (PRCC) (SAMETA)

Studio di fase III, in aperto, randomizzato, a 3 bracci, multicentrico su savolitinib più durvalumab rispetto a sunitinib e durvalumab in monoterapia in partecipanti con carcinoma a cellule renali papillari (CCRp) indotto da MET, non resecabile e localmente avanzato o metastatico (SAMETA)

A.3.1

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

A clinical trial to compare the effectiveness of savolitinib plus durvalumab relative to sunitinib for the treatment of renal cell cancer.

Uno studio clinico per confrontare l'efficacia di savolitinib più durvalumab rispetto a sunitinib per il trattamento del cancro delle cellule renali.

A.3.2

Name or abbreviated title of the trial where available

SAMETA

A.4.1

Sponsor's protocol code number

D5086C00001

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	ASTRAZENECA AB
B.1.3.4	Country	Sweden
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	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca
B.5.2	Functional name of contact point	Information Center
B.5.3	Address:
B.5.3.1	Street Address	N/A
B.5.3.2	Town/ city	N/A
B.5.3.3	Post code	N/A
B.5.3.4	Country	United States
B.5.4	Telephone number	+13028851180
B.5.6	E-mail	information.center@astrazeneca.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	Savolitinib
D.3.2	Product code	[AZD6094, HMPL-504]
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	savolitinib
D.3.9.1	CAS number	1313725-88-0
D.3.9.2	Current sponsor code	AZD6094
D.3.9.3	Other descriptive name	1-[(S)-1-(imidazo[1,2-a]pyridin-6-yl)ethyl]-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]- triazolo[4,5-b]pyrazine
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: 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	Durvalumab
D.3.2	Product code	[MEDI4736]
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	DURVALUMAB
D.3.9.1	CAS number	1428935-60-7
D.3.9.2	Current sponsor code	MEDI4736
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	50
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	Sutent 25 mg hard capsules
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Europe MA EEIG
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	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	sunitinib malate
D.3.9.1	CAS number	341031-54-7
D.3.9.2	Current sponsor code	NA
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	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Sutent 12.5 mg hard capsules
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Europe MA EEIG
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	sunitinib malate
D.3.9.1	CAS number	341031-54-7
D.3.9.2	Current sponsor code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	12500
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	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	infliximab 100 mg powder for concentrate for solution for infusion
D.3.2	Product code	[NA]
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	infliximab
D.3.9.2	Current sponsor code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	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: 6
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	Micofenolato capsule 250 mg
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	Micofenolato mofetile
D.3.9.2	Current sponsor code	NA
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	250
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

MET-driven, unresectable and locally advanced or metastatic Papillary Renal Cell Carcinoma

carcinoma a cellule renali papillari (CCRp) indotto da MET, non resecabile e localmente avanzato o metastatico

E.1.1.1

Medical condition in easily understood language

unresectable and locally advanced or metastatic renal cell cancer

carcinoma alle cellule renali non resecabile e localmente avanzato o metastatico

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 demonstrate the effectiveness of savolitinib plus durvalumab relative to sunitinib by assessment of progression-free survival (PFS) in participants with MET-driven, unresectable and locally advanced or metastatic PRCC.

Dimostrare l’efficacia di savolitinib più durvalumab rispetto a sunitinib mediante la valutazione di PFS in partecipanti con CCRp indotto da MET, non resecabile e localmente avanzato o metastatico.

E.2.2

Secondary objectives of the trial

a. To demonstrate the effectiveness of savolitinib plus durvalumab relative to sunitinib in participants with MET-driven, unresectable and locally advanced or metastatic PRCC by the assessment of :
- overall survival (OS)
- objective response rate (ORR)
- duration of response (DoR)
- disease control rate (DCR) at 24 and 48 weeks
- time from randomisation to second progression or death (PFS2)
b. To demonstrate the effectiveness of savolitinib plus durvalumab relative to durvalumab monotherapy in participants with MET-driven, unresectable and locally advanced or metastatic PRCC by assessment of :
- ORR
- DoR
- PFS
c. To assess patient-reported symptoms, functioning, and HRQoL in participants with MET-driven, unresectable and locally advanced or metastatic PRCC treated with savolitinib plus durvalumab relative to sunitinib
d. To evaluate the PK of savolitinib and durvalumab in participants with MET-driven, unresectable and locally advanced or metastatic PRCC.

a. Dimostrare l’efficacia di savolitinib più durvalumab rispetto a sunitinib in partecipanti con CCRp indotto da MET, non resecabile e localmente avanzato o metastatico mediante la valutazione di:
- sopravvivenza globale (OS)
- tasso di risposta obiettiva (ORR)
- durata della risposta (DoR)
- tasso di controllo della malattia (DCR) a 24 o 48 settimane
- tempo dalla randomizzazione alla seconda progressione o al decesso (PFS2)
b. Dimostrare l’efficacia di savolitinib più durvalumab rispetto a durvalumab in monoterapia in partecipanti con CCRp indotto da MET, non resecabile e localmente avanzato o metastatico mediante la valutazione di:
- ORR
- DoR
- PFS
c. Valutare i sintomi riferiti dal paziente, funzionalità e HRQoL in partecipanti con CCRp indotto da MET, non resecabile e localmente avanzato o metastatico, trattati con savolitinib più durvalumab rispetto a sunitinib.
d. Valutare la farmacocinetica di savolitinib e durvalumab nei partecipanti con CCRp indotto da MET

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Histologically confirmed unresectable and locally advanced or metastatic PRCC
• PRCC must be centrally confirmed as MET-driven using a sponsor-designated central laboratory validated NGS assay
• No prior systemic anti-cancer treatment in the metastatic setting; no prior exposure to MET inhibitors, Durvalumab or Sunitinib in any setting
• Karnofsky Score >70
• At least one lesion, not previously irradiated, that can be accurately measured at baseline
• Adequate organ and bone marrow function
• Life expectancy >=12weeks at Day 1

• CCRp istologicamente confermato non resecabile e localmente avanzato o metastatico
• Il CCRp deve essere confermato a livello centrale che sia indotto da MET utilizzando un test NGS convalidato dal laboratorio centrale designato dallo sponsor
• Nessun trattamento antitumorale sistemico precedente nel contesto metastatico; nessuna precedente esposizione ad inibitori MET, Durvalumab o Sunitinib in qualsiasi contesto
• Punteggio Karnofsky> 70
• Almeno una lesione, non precedentemente irradiata, che possa essere accuratamente misurata al basale
• Adeguata funzionalità degli organi e del midollo osseo
• Aspettativa di vita >=12 settimane al giorno 1

E.4

Principal exclusion criteria

• History of serious liver disease, with or without, normal LFTs, such as cirrhosis or Wilson’s disease
• Spinal cord compression or brain metastases, unless asymptomatic and stable on treatment for at least 14 days prior to study intervention
• Active or prior cardiac disease (within past 6 months) or clinically significant ECG abnormalities and/or factors/medications that may affect QT and/or QTc intervals
• Active infection including HIV, TB, HBV and HCV
• Active or prior documented autoimmune or inflammatory disorders
• Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention

• Anamnesi di grave malattia del fegato, con o senza, normali Test della funzionalità epatica, come cirrosi o morbo di Wilson
• Compressione del midollo spinale o metastasi cerebrali, a meno che non siano asintomatiche
e stabile durante il trattamento per almeno 14 giorni prima dell'intervento in studio
• Cardiopatia attiva o pregressa (negli ultimi 6 mesi) o clinicamente anomalie ECG significative e / o fattori / farmaci che possono influenzano gli intervalli QT e / o QTc
• Infezione attiva inclusi HIV, TB, HBV e HCV
• Disturbi autoimmuni o infiammatori attivi o documentati in precedenza
• Ricezione del vaccino vivo attenuato entro 30 giorni prima della prima dose dell'intervento di studio

E.5 End points

E.5.1

Primary end point(s)

PFS is defined as time from randomisation until disease progression per RECIST 1.1 as assessed by blinded independent central review (BICR), or death due to any cause.

La sopravvivenza libera da progressione (PFS) è definita come il tempo dalla randomizzazione alla progressione secondo i criteri RECIST 1.1, come valutato mediante BICR, o al decesso per qualsiasi causa

E.5.1.1

Timepoint(s) of evaluation of this end point

PFS: disease progression or death
PFS is planned to be analyzed at approximately 28 months after the first patient randomized (DCO1).

PFS: progressione della malattia o morte
La PFS dovrebbe essere analizzata a circa 28 mesi dopo la randomizzazione del primo partecipante (DCO1).

E.5.2

Secondary end point(s)

a. and b. :
- OS is defined as time from randomisation until the date of death due to any cause.
- ORR is defined as the proportion of participants who have a complete response (CR) or partial response (PR) as determined by BICR per RECIST 1.1.
- DoR will be defined as the time from the date of first documented response until date of documented progression per RECIST 1.1 as assessed by BICR or death due to any cause.
- DCR at 24 or 48 weeks is defined as the percentage of participants who have a CR or PR or who have stable disease (SD) per RECIST 1.1 as assessed by BICR for at least 23 or 47 weeks, respectively after randomisation.
- PFS2 will be defined as time from randomisation to the earliest of the progression event (following the initial progression), subsequent to the first subsequent therapy or death.
- PFS is defined as time from randomisation until disease progression per RECIST 1.1 as assessed by blinded independent central review (BICR), or death due to any cause.

c. Time to deterioration and change from baseline in symptoms, functioning, and HRQoL as measured by FKSI-19.

d. The measures of interest are as follows:
- participants randomised to savolitinib plus durvalumab : plasma concentration of savolitinib and its metabolites pre-dose (Ctrough) and post-dose (C1h and C3h), serum concentration of durvalumab pre-dose (Ctrough) and at the end of infusion (Cmax)
- participants randomised to durvalumab monotherapy : serum concentration of durvalumab pre-dose (Ctrough) and at the end of infusion (Cmax)

a. e b.:
- La sopravvivenza globale (OS) viene definita come tempo trascorso dalla data della randomizzazione al decesso per qualsiasi causa.
- Il tasso di risposta obiettiva (ORR) è definito come la percentuale di partecipanti che presentano una CR o PR determinata mediante BICR secondo i criteri RECIST 1.1.
- La durata della risposta (DoR) sarà definita come l’intervallo di tempo dalla data della prima risposta documentata alla data della progressione documentata secondo i criteri RECIST 1.1, valutata mediante BICR, o del decesso per qualsiasi causa.
- Il tasso di controllo della malattia (DCR) a 24 o 48 settimane è definito come la percentuale di partecipanti che presentano una CR o PR o SD secondo i criteri RECIST 1.1 come valutato mediante BICR per almeno 23 o 47 settimane, rispettivamente dopo la randomizzazione.
- Il tempo dalla randomizzazione alla seconda progressione o al decesso (PFS2) sarà definito come il tempo dalla randomizzazione al primo evento di progressione (dopo la progressione iniziale), successivo alla prima terapia successiva o al decesso.
- La PFS è definita come il tempo dalla randomizzazione fino alla progressione della malattia o alla morte per qualsiasi causa secondo RECIST 1.1 come valutato da BICR.

c. Tempo al peggioramento e variazione rispetto al basale nei sintomi, nella funzionalità e nell’HRQoL, misurati mediante FKSI-19.

d. Le misure di interesse sono le seguenti:
- Concentrazione plasmatica di savolitinib e dei suoi metaboliti pre-dose (Cminima) e post-dose (C1ora e C3ore) nei partecipanti randomizzati a savolitinib più durvalumab, Concentrazione sierica di durvalumab pre-dose (Cminima) e alla fine dell’infusione (Cmax) nei partecipanti randomizzati a savolitinib più durvalumab o durvalumab in monoterapia.

E.5.2.1

Timepoint(s) of evaluation of this end point

a. and b. :
- OS: date of death
- ORR: first objective response (complete or partial)
- DoR: first documented response until date of documented progression or death
- DCR : 24 or 48 weeks after randomization
- PFS2: the earliest of progression event subsequent to first subsequent therapy or death
- PFS: disease progression or death
These are planned to be analyzed at approximately 28 months after the first patient randomized (DCO1). In addition, for OS secondly once OS data has reached planned, approximately 42 months post first subject randomized (DCO2).

c. Day 1 of each cycle
d. Please refer to the schedule of activities in the study protocol
"c" and "d" are planned to be analyzed at approximately 28 months after the first patient randomized (DCO1).

a. e b. :
- OS: data della morte
- ORR: prima risposta oggettiva (completa o parziale)
- DoR: prima risposta documentata fino alla data di progressione documentata o di morte
- DCR: 24 o 48 settimane dopo la randomizzazione
- PFS2: il primo evento di progressione successivo alla prima terapia successiva o al decesso
- PFS: progressione della malattia o morte
Questi dovrebbero essere analizzati a circa 28 mesi dopo il primo partecipante randomizzato (DCO1). Inoltre, per l'OS in secondo luogo, una volta che i dati dell'OS hanno raggiunto il previsto, circa 42 mesi dopo il primo soggetto randomizzato (DCO2).

c. Giorno 1 di ogni ciclo
d. Fare riferimento al programma delle attività nel protocollo di studio
[..]

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

Yes

E.6.11

Pharmacogenomic

Yes

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

Yes

E.8.1.6

Cross over

Yes

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

Brazil

Canada

Chile

China

Hong Kong

India

Israel

Korea, Republic of

Mexico

Russian Federation

Singapore

Taiwan

Turkey

Ukraine

United States

France

Germany

Italy

Netherlands

Poland

Romania

Spain

United Kingdom

Czechia

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

last visit of the last participant in the study

ultima visita dell'ultimo paziente nello studio

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:

120

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Adult participant with authorised legal representative

Partecipanti adulti con rappresentante legale autorizzato

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

200

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)

After the final DCO for this trial (DCO2), Sponsor will be able to continue to supply trial intervention (ie, savolitinib plus durvalumab, durvalumab monotherapy, sunitinib, or savolitinib monotherapy [if durvalumab was stopped earlier]) to subjects who are ongoing on those treatments at DCO2 as long as, in the opinion of the investigator, they are still receiving clinical benefit or until meeting any other discontinuation criteria. They will be monitored according to routine clinical practice.

Dopo il DCO finale per questo studio (DCO2), lo Sponsor potrà continuare a fornire l'IMP dello studio (ad esempio, savolitinib più durvalumab, durvalumab in monoterapia, sunitinib o savolitinib in monoterapia [se durvalumab è stato interrotto prima]) ai soggetti che presentano tali trattamenti in corso al DCO2 fintanto che, a parere dello sperimentatore, ricevino benefici clinici o fino a quando non soddisfino altri criteri di interruzione. Saranno monitorati secondo la pratica clinica.

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

2021-08-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-06-30

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

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Orphan Designation Number:
Results Status:
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