Clinical Trials Register

Summary
EudraCT Number:	2018-001384-23
Sponsor's Protocol Code Number:	65512-SAFESTOP
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2018-06-07
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

Netherlands - Competent Authority

A.2

EudraCT number

2018-001384-23

A.3

Full title of the trial

Safe Stop Trial: observational study of the STOP & GO strategy of PD-1 blockade in advanced melanoma patients upon achieving a complete or partial response

Safe Stop Studie: observationele studie van de STOP & GO strategie van PD-1 blokkade bij patiënten met een gevorderd melanoom bij het bereiken van een complete of partiële respons

A.3.1

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

Observational trial to investigate whether patients with advanced melanoma who experience a tumor respons during treatment with nivolumab or pembrolizumab, can safely stop this treatment early

Het eerder staken van nivolumab of pembrolizumab bij patiënten met gevorderd melanoom die goed reageren op deze behandeling

A.3.2

Name or abbreviated title of the trial where available

SAFE STOP trial melanoma

SAFE STOP studie melanoom

A.4.1

Sponsor's protocol code number

65512-SAFESTOP

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	Erasmus Medical Center
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Health Insurance Zilveren Kruis
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Health Insurance CZ
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Health Insurance VGZ
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Health Insurance Menzis
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Erasmus Medical Center
B.5.2	Functional name of contact point	Dr. A.A.M. van der Veldt
B.5.3	Address:
B.5.3.1	Street Address	's-Gravendijkwal 230
B.5.3.2	Town/ city	Rotterdam
B.5.3.3	Post code	3015CE
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031(0)107041754
B.5.6	E-mail	a.vanderveldt@erasmusmc.nl

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	Opdivo
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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.3.4	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	NIVOLUMAB
D.3.9.3	Other descriptive name	NIVOLUMAB
D.3.9.4	EV Substance Code	SUB122750
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Keytruda
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme (MSD)
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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.3.4	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	PEMBROLIZUMAB
D.3.9.1	CAS number	1374853-91-4
D.3.9.4	EV Substance Code	SUB167136
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

malignant and not otherwise specified skin neoplasms

huidneoplasmata maligne en niet-gespecificeerd

E.1.1.1

Medical condition in easily understood language

malignant melanoma

maligne melanoom

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	20.0
E.1.2	Level	HLGT
E.1.2	Classification code	10040900
E.1.2	Term	Skin neoplasms malignant and unspecified
E.1.2	System Organ Class	10040785 - Skin and subcutaneous tissue disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to evaluate ongoing responses in patients with advanced and metastatic melanoma who discontinue first-line monotherapy with nivolumab or pembrolizumab upon achieving CR or PR according to RECIST v1.1

Het primaire eindpunt is het aantal voortdurende tumorresponsen (CR en PR) volgens RECIST v1.1 bij 24 maanden sinds de eerste start van nivolumab of pembrolizumab.

E.2.2

Secondary objectives of the trial

The secondary endpoints include:
1a. Total duration of response after first documented CR or PR followed by treatment interruption
1b. Duration of response (CR and PR) after discontinuation of nivolumab or pembrolizumab
2. Progression-free survival (PFS) from start of nivolumab/pembrolizumab (PFS1)
3a. Rate of reintroduction of nivolumab/pembrolizumab upon first PD
3b. Failure rate of reintroducing nivolumab/pembrolizumab and the need for other salvage therapy at first PD
4. Best response on rechallenge with nivolumab/pembrolizumab
5. PFS after reintroduction of nivolumab/pembrolizumab (PFS2)
6a. Total PFS (including period after discontinuation and reintroduction of nivolumab/pembrolizumab)
6b. Overall survival (OS)
7a. Rate of grade 3-4 adverse events (AEs) after discontinuation of nivolumab/pembrolizumab
7b. Rate of grade 3-4 adverse events (AEs) after reintroduction of nivolumab/pembrolizumab

1a. Totale responsduur vanaf de eerst gedocumenteerde CR of PR voor het staken van de behandeling
1b. Responsduur na het staken van nivolumab of pembrolizumab
2. Progressie vrije overleving (PFS) vanaf het starten van nivolumab/pembrolizumab (PFS1)
3a. Mate van herstart nivolumab/pembrolizumab bij eerst gedocumenteerde progressieve ziekte (PD)
3b. Mate van falen na herstart nivolumab/pembrolizumab en de noodzaak voor een andere behandeling bij eerste PD
4. Beste respons na herstart van nivolumab/pembrolizumab
5. PFS na herstart van nivolumab/pembrolizumab (PFS2)
6a. Totale PFS (inclusief periode na staken en bij herstart van nivolumab/pembrolizumab)
6b. Totale overleving (OS)
7a. Mate van graad 3-4 bijwerkingen na staken nivolumab/pembrolizumab
7b. Mate van graad 3-4 bijwerkingen na herstart nivolumab/pembrolizumab

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- advanced or metastatic melanoma
- current treatment with first-line nivolumab or pembrolizumab for advanced or metastatic melanoma
- having confirmed complete remission (CR) or partial response (PR) according to RECIST v.1.1
- planned to discontinue nivolumab or pembrolizumab within 4 weeks after confirmation of CR or PR before the full period of 2 years therapy

- gevorderd of gemetastaseerd melanoom
- momenteel eerstelijns behandeling met nivolumab or pembrolizumab voor gevorderd of gemetastaseerd melanoom
- bevestigde complete remissie (CR) of partiële respons (PR) volgens RECIST v.1.1
- gepland om nivolumab or pembrolizumab eerder te discontinueren binnen 4 weken na bevestigde CR of PR, voor een totale behandelduur van 2 jaar

E.4

Principal exclusion criteria

Concomitant systemic therapies with other anti-cancer agents, e.g. BRAF-inhibitor, anti-CTLA4 (e.g. ipilimumab), or other PD-1 blockade than nivolumab or pembrolizumab

Gelijktijdige behandeling met andere anti-kanker middelen, zoals BRAF-remmers, anti-CTLA4 (bijv. ipilimumab) of andere PD-1 blokkade (dan nivolumab of pembrolizumab)

E.5 End points

E.5.1

Primary end point(s)

Rate of ongoing responses (CR and PR) according to RECIST v1.1 at 24 months after first start of nivolumab or pembrolizumab

Aantal voortdurende tumorresponsen (CR en PR) volgens RECIST v1.1 bij 24 maanden sinds de eerste start van nivolumab of pembrolizumab

E.5.1.1

Timepoint(s) of evaluation of this end point

24 months after last patient included

24 maanden nadat de laatste patient is geincludeerd

E.5.2

Secondary end point(s)

1a. Total duration of response after first documented CR or PR followed by treatment interruption
1b. Duration of response (CR and PR) after discontinuation of nivolumab or pembrolizumab
2. Progression-free survival (PFS) from start of nivolumab/pembrolizumab (PFS1)
3a. Rate of reintroduction of nivolumab/pembrolizumab upon first PD
3b. Failure rate of reintroducing nivolumab/pembrolizumab and the need for other salvage therapy at first PD
4. Best response on rechallenge with nivolumab/pembrolizumab
5. PFS after reintroduction of nivolumab/pembrolizumab (PFS2)
6a. Total PFS (including period after discontinuation and reintroduction of nivolumab/pembrolizumab)
6b. OS
7a. Rate of grade 3-4 adverse events (AEs) after discontinuation of nivolumab/pembrolizumab
7b. Rate of grade 3-4 adverse events (AEs) after reintroduction of nivolumab/pembrolizumab

E.5.2.1

Timepoint(s) of evaluation of this end point

60 months after last patient has started treatment

60 maanden nadat de laatste patient startte met behandeling

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

E.6.7

Pharmacodynamic

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

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Yes

E.8.1.7.1

Other trial design description

observationeel

observational

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.8.3

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.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

Mortality and diagnosis of new symptomatic brain metastases in patients without PD-1 blockade will be reported expedited as Events of Clinical Interest (ECI's). Taking into account up-to-date literature, the DSMB will review these, report their findings to the principal investigator and advise on study continuation after 75 patients are included; 6-monthly DSMB evaluations will be added if necessary until the DSMB has confirmed that the provided data are mature or until 200 patients are included

Overlijden en optreden van nieuwe hersenmetastasen bij patiënten die op dat moment geen PD-1 blockade gebruiken dienen versneld gemeld te worden als Event of Clinical Interest (ECI).
De onafhankelijke data monitoring commissie zal deze beoordelen en op basis hiervan en de actuele literatuur adviseren om de trial te (dis)continueren na 75 geincludeerde patiënten en indien nodig nadien halfjaarlijks totdat 200 patienten zijn geincludeerd.

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:

200

F.1.3

Elderly (>=65 years)

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

F.3.3.1

Women of childbearing potential not using contraception

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

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)

Standard of care

Standaard behandeling

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	WIN-O (Werkgroep Immunotherapie Nederland voor Oncologie)

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-06-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-11-08

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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