Clinical Trials Register

Summary
EudraCT Number:	2016-004108-73
Sponsor's Protocol Code Number:	D5082C00003
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-02-11
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

2016-004108-73

A.3

Full title of the trial

A Phase III, Open Label, Randomised, Controlled, Multi-Centre Study To Assess the Efficacy and Safety of Savolitinib versus Sunitinib in Patients with MET-Driven, Unresectable/Locally Advanced Or Metastatic Papillary Renal Cell Carcinoma (PRCC)

A Phase III, Open Label, Randomised, Controlled, Multi-Centre Study To Assess the Efficacy and Safety of Savolitinib versus Sunitinib in Patients
with MET-Driven, Unresectable/Locally Advanced Or Metastatic Papillary Renal Cell Carcinoma (PRCC)

A.3.1

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

A phase III study to compare the efficacy and safety of a new anticancer medication, Savolitinib, with another medication, Sunitinib, in patients with a kind of papillary renal cell carcinoma (PRCC) that is considered “MET-driven” based on defined genetic abnormalities and cannot be completely surgically removed and/or has spread to at least one other part of the body

Studio di Fase III, in aperto, randomizzato, controllato, multicentrico per valutare l’efficacia e la Sicurezza di Savolitinib vs Sunitinib, in pazienti con mutazione del gene MET nel Carcinoma a Cellule Renali di tipo Papillare (PRCC), non resecabile e Localmente Avanzato o Metastatico

A.3.2

Name or abbreviated title of the trial where available

A phase III study to compare the efficacy and safety of a new anticancer medication, Savolitinib, wi

Studio di Fase III, in aperto, randomizzato, controllato, multicentrico per valutare l’efficacia e l

A.4.1

Sponsor's protocol code number

D5082C00003

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03091192

A.5.4

Other Identifiers

Name:

SAVOIR

Number:

D5082C00003

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 SPA
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
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Hutchison Medi Pharma
B.4.2	Country	China
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca AB
B.5.2	Functional name of contact point	Clinical Trial Transparency
B.5.3	Address:
B.5.3.1	Street Address	Karlebyhus, Astraallen
B.5.3.2	Town/ city	Sodertajle
B.5.3.3	Post code	SE 151 85
B.5.3.4	Country	Sweden
B.5.4	Telephone number	n/a
B.5.5	Fax number	n/a
B.5.6	E-mail	clinicaltrialtransparency@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	.
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
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	.
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	200 to 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	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
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer limited
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	Sunitinib
D.3.2	Product code	37192046
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SUNITINIB MALEATO
D.3.9.1	CAS number	341031-54-7
D.3.9.2	Current sponsor code	.
D.3.9.3	Other descriptive name	SUNITINIB MALEATO
D.3.10	Strength
D.3.10.1	Concentration unit	mg/l milligram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	12.5
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	Sutent
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Limited
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	Sunitinib
D.3.2	Product code	37192046
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SUNITINIB MALEATO
D.3.9.1	CAS number	341031-54-7
D.3.9.2	Current sponsor code	.
D.3.9.3	Other descriptive name	SUNITINIB MALEATO
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	25.0
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

papillary renal cell carcinoma (PRCC)

Carcinoma alle cellule papillari renali

E.1.1.1

Medical condition in easily understood language

renal cell cancer

Cancro alle cellule renali

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	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10023400
E.1.2	Term	Kidney cancer
E.1.2	System Organ Class	100000004864

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 determine the efficacy of savolitinib when compared to sunitinib in patients with MET-driven, unresectable/locally advanced or metastatic PRCC.

Determinare l’efficacia di savolitinib versus sunitinib in pazienti con alterazione del gene MET con PRCC , non asportabile, localmente avanzato o metastatico.

E.2.2

Secondary objectives of the trial

- To compare the efficacy of savolitinib versus sunitinib in patients with MET-driven, unresectable/locally advanced or metastatic PRCC
- To assess the impact of savolitinib and sunitinib on disease related symptoms and health-related QOL in this patient population
- To evaluate the pharmacokinetics of savolitinib in this patient population

Determinare l’efficacia di savolitinib versus sunitinib in pazienti con alterazione del gene MET con PRCC , non asportabile, localmente avanzato o metastatico.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Histologically confirmed PRCC, which is unresectable/locally advanced or metastatic with measurable disease as per RECIST 1.1.
2. Confirmation of MET-driven PRCC without co-occurring FH or VHL mutations from an FFPE tumour sample using the sponsor-designated central laboratory
validated MET NGS assay
3. Patients who have received no prior systemic therapy as well as those who have received prior systemic therapy for PRCC
4. Adequate haematological, renal, cardiac and liver functions
5. Karnofsky performance status ≥ 80

1. PRCC confermato istologicamente, non resecabile e localmente avanzato, o
Metastatico. I pazienti devono avere tumore misurabile dalla TAC di base secondo RECIST 1.1.
2.Conferma di PRCC con mutazione del gene MET in assenza di mutazioni FH o VHL da un campione del blocchetto tumorale incluso in paraffina utilizzando il laboratorio centrale designato dallo sponsor convalidato tramite test di sequenziamento di nuova generazione per il gene MET .
3. Pazienti che non hanno ricevuto precedenti terapie sistemiche così come pazienti che hanno ricevuto una precedente terapia sistemica per il PRCC
4. Adeguate funzioni ematologiche, renali, cardiache ed epatiche
5. Performance status secondo Karnofsky ≥80.

E.4

Principal exclusion criteria

1. Most recent cytotoxic chemotherapy, immunotherapy, chemo-immunotherapy, or investigational agents <21 days from the date of randomisation or 5 half-lives of the agent, whichever is longer. Most recent non-cytotoxic targeted therapy <14 days from the date of randomisation.
2. Prior treatment with a MET inhibitor (e.g. foretinib, crizotinib, cabozantinib, onartuzumab or previous savolitinib) or sunitinb.
3. Treatment with strong inducers or inhibitors of CYP3A4 or strong inhibitors of CYP1A2, taken within 2 weeks or not possible to be stopped for at least 2 week before the date of randomisation. Herbal medications cannot be taken within 7 days of the date of randomisation (3 weeks for St John’s wort).
3. Wide field radiotherapy administered ≤28 days or limited field radiation for palliation ≤7 days prior to the date of randomisation
4. Major surgical procedures ≤28 days of randomisation or minor surgical procedures ≤7 days. No waiting is required following port-a-cath placement.
5. Previously untreated brain metastases
6. Serious active infection or gastrointestinal disease
7. Presence of other active cancers, or history of treatment for invasive cancer within the last 5 years.

1.Il trattamento più recente con farmaci chemioterapici citotossici, immunoterapia, chemio-immunoterapia, o farmaci sperimentali risalente a < 21 giorni dalla data di randomizzazione o il trattamento con agenti con emivita di 5 ore, anche se più lungo. La più recente terapia mirata non citotossica risalente a < 14 giorni dalla data di randomizzazione.

2.in caso di Trattamento precedente con un inibitore del gene MET (ad esempio foretinib, crizotinib, cabozantinib, Onartuzumab o precedente savolitinib) o sunitinb*.

3.in caso di Trattamento con induttori forti o inibitori di CYP3A4 o forti inibitori di CYP1A2, assunti entro due settimane o se non è possibile stoppare per almeno 2 settimane prima della data di randomizzazione. I farmaci a base di erbe non possono essere assunti nei 7 giorni precedenti la data di randomizzazione (3 settimane per l’Erba di San Giovanni). Vedi Appendice H.

4.Radioterapia ad ampio campo (inclusi radioisotopi terapeutici come lo stronzio 89) somministrato ≤28 giorni o radiazioni a campo limitato come palliativo ≤7 giorni prima della data della randomizzazione o se non c’è stato recupero dagli effetti collaterali di tale terapia.

5.Principali procedure chirurgiche avvenute ≤ 28 giorni di randomizzazione o procedure chirurgiche minori ≤7 giorni. Non è richiesta alcuna attesa dopo il posizionamento del port-a-cath.

6. In caso di metastasi al cervello non trattate

7. In caso di infezioni serie o di malattie gastrointestinali attive o altre condizioni che interferiscono in modo significativo
Con l'assorbimento, la distribuzione, il metabolismo, o l'escrezione della terapia orale
Presenza di altri tumori attivi, o storia del trattamento per il cancro invasivo, negli ultimi 5 anni.

E.5 End points

E.5.1

Primary end point(s)

Progression-Fress Survival (PFS) using Blinded Independent Central Review (BICR) assessments according to RECIST 1.1 or death

E.5.1.1

Timepoint(s) of evaluation of this end point

Every 6 weeks, corresponding to the start of each cycle during the first year and then every 12 weeks thereafter, until BICR-confirmed progression using RECIST 1.1.

E.5.2

Secondary end point(s)

- Overall Survival (OS)
- Objective Response Rate (ORR), duration of response (DoR) and best percentage change in tumour size by BICR using RECIST 1.1 criteria
- Disease Control Rate (DCR) at 6 and 12 months
-Mean change from baseline in FKSI-19 and FACIT-F scores
- PK concentration data

E.5.2.1

Timepoint(s) of evaluation of this end point

- OS - at least every 12 weeks following second PD by institutional call (or following discontinuation of study medication for PD by RECIST 1.1 if a patient not continuing on post-progression study treatment) until death, lost to follow-up, or withdrawal of consent, whichever comes first
- ORR, DoR, DCR or best percentage change in tumour size - Every 6 weeks, corresponding to the start of each cycle during the first year and then every 12 weeks thereafter, until BICR-confirmed progression using RECIST 1.1.
- PK - Cycle 1 Day 1 (Pre-Dose); Cycle 1 Day 15 (Pre-Dose, and 1 and 3 hours post-dosing); Cycle 1 Day 29 (Pre-Dose); Cycle 2 Day 15 (Pre-Dose); At the time that the patient is diagnosed with abnormal LFTs necessitating drug discontinuation.

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

Yes

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

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

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

Brazil

Korea, Republic of

Russian Federation

Ukraine

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

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

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

Yes

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

180

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)

None

nessuno

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

2017-12-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-09-25

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
Orphan Designation Number:
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