Clinical Trials Register

Summary
EudraCT Number:	2013-000773-71
Sponsor's Protocol Code Number:	vem+IL-2v1.0
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-07-12
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

Denmark - DHMA

A.2

EudraCT number

2013-000773-71

A.3

Full title of the trial

A multicenter phase II study evaluating the efficacy and tolerability of vemurafenib in combination with Pegylated Interferon and Interleukin-2 in patients with BRAF-mutated metastatic melanoma

Et multicenter fase II studie af effekten og tolerabiliteten af vemurafenib kombineret med Pegyleret Interferon og Interleukin-2 til patienter med BRAF-muteret metastatisk melanom

A.3.1

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

A multicenter phase II study evaluating the effect and tolerability of vemurafenib in combination with Pegylated Interferon and Interleukin-2 in patients with metastatic melanoma positive for the BRAF-mutation

En multicenter fase II undersøgelse af vemurafenib i kombination med Pegyleret Interferon og Interleukin-2 til patienter med BRAF-muteret metastatisk malignt melanom

A.3.2

Name or abbreviated title of the trial where available

vem+IL-2

A.4.1

Sponsor's protocol code number

vem+IL-2v1.0

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	Department of Oncology, Aarhus University Hospital
B.1.3.4	Country	Denmark
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	Aarhus University Hospital
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Odense University Hospital
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	Copenhagen University Hospital at Herlev uøniversity Hospital
B.4.2	Country	Denmark
B.4.1	Name of organisation providing support	F.HOFFMANN-LA ROCHE LTD
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Department of Oncology, Aarhus University Hospital
B.5.2	Functional name of contact point	Henrik Schmidt
B.5.3	Address:
B.5.3.1	Street Address	Norrebrogade 44
B.5.3.2	Town/ city	Aarhus
B.5.3.3	Post code	8000
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+4578461682
B.5.5	Fax number	+4578462530
B.5.6	E-mail	henrschm@rm.dk

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	Zelboraf
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Zelboraf
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	vemurafenib
D.3.9.1	CAS number	918504-65-1
D.3.9.3	Other descriptive name	VEMURAFENIB
D.3.9.4	EV Substance Code	SUB32161
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	240
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	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	Proleukin
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Pharmaceuticals UK Limited
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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 injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous drip use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	aldesleukin
D.3.9.1	CAS number	110942-02-4
D.3.9.3	Other descriptive name	ALDESLEUKIN
D.3.9.4	EV Substance Code	SUB05303MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	18000000
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	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)	Yes
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	Yes
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	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	PegIntron
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck, Sharp and Dohme Limited
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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 and solvent for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	peginterferon alfa-2b
D.3.9.3	Other descriptive name	PEGINTERFERON ALFA-2B
D.3.9.4	EV Substance Code	SUB12549MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
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	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)	Yes
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	Yes
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

Metastatic melanoma

Metastatisk malignt melanom

E.1.1.1

Medical condition in easily understood language

Disseminated malignant melanoma

Udbredt modermærkekræft

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	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10027481
E.1.2	Term	Metastatic melanoma
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 evaluate 6 month progression free-survival (PFS) rate of vemurafenib in combination with interleukin-2 (IL-2) and pegylated interferon (IFN) in patients with BRAF-mutated metastatic melanoma

At evaluere progressions fri overleve (PFS) efter 6 måneder blandt patienter med BRAF-muteret metastatisk malignt melanom ved behandling med vemurafenib i kombination med interleukin-2 (IL-2) og pegyleret interferon (IFN)

E.2.2

Secondary objectives of the trial

•To evaluate the safety and tolerability of vemurafenib in combination with IL-2/IFN
•To evaluate 1-year survival rate (OS)
•To evaluate overall response rates as defined by RECIST v.1.1
•To evaluate the number of long-term survivors by estimating the 5-year survival rate
•To evaluate predictive and prognostic biomarkers for response and survival

•Evaluere sikkerheden og tolerabiliteten ved behandling med vemurafenib i kombination med IL-2/IFN
•Evaluere 1-års overlevelses raten
•Evaluere respons raten i henhold til RECIST v.1.1
•Evaluere andelen af langtids overlevere ved at estimere 5-års overlevelsen
•Evaluere prediktive og prognostiske biomarkører for respons og overlevelse

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Histologically verified unresectable stage III or stage IV melanoma with documented BRAF V600 mutation determined by the cobas® 4800 BRAF mutation test
•Age between 18 and 70
•ECOG performance status (PS) 0-2
•Patients must have measurable target lesions disease as defined by RECIST v1.1
•Prior medical treatment for metastatic melanoma is allowed, except previous treatment with BRAF-inhibitor and IL-2 based immunotherapy
•Adequate cardiac function (less or equal to NYHA II). In the case of previous myocardial infarction echocardiography or MUGA-scan must be performed and left ventricle ejection fraction must be found normal
•Adequate hematologic, renal and liver function as defined by laboratory values performed within 2 weeks of enrolment:
o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
o Platelet count ≥ 100 x 109/L
o Serum creatinine ≤ 1.5 times upper limit of normal (ULN) or - creatinine clearance (CrCl) > 50 mL/hr by Cockroft–Gault formula
o Alanine aminotransferase (ALAT) ≤ 2.5 times ULN (≤ 5 times ULN if considered due to liver metastasis)
o Serum bilirubin ≤ 1.5 times ULN
o Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN if considered due to liver metastasis)
•Patients must have absence of any underlying medical or psychiatric condition, which in the opinion of the investigator, will make the administration of the study drugs hazardous or obscure the interpretation of adverse events
•Fertile men and women must be using an effective method of contraception during treatment and for at least one month after completion of treatment
•Women of child-bearing potential (WOCBP) must have a negative pregnancy test (HCG-urinalysis) before trial entry
•Signed informed consent must be obtained prior to performing any study-related procedures. Testing for the V600 BRAF-mutation is considered as a standard procedure

E.4

Principal exclusion criteria

•Any known severe and symptomatic autoimmune diseases that upon the opinion of the Investigators may conflict with the administration of the study medication.
•Cerebral metastases. Patients that have been radically treated (neurosurgery or stereotactic radiotherapy) for a solitary cerebral metastasis may be included if MRI of the brain performed at least one month after treatment is without evidence of disease activity
•Patients must not be dependent on systemic treatment with corticosteroids or other immunosuppressing agents
•Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that may compromise adequate absorption. Patients must be able to swallow tablets
•Uncontrolled infectious disease (requiring treatment with intravenous antibiotics)
•Second malignancy in the past 5 years with the exception of surgically cured carcinoma in situ of the cervix or basal and squamous cell carcinoma of the skin.
•QTc-interval > 500 ms
•Any psychological, familial, sociological or geographical condition that upon the opinion of the investigators may affect the compliance with the protocol and follow-up schedule

E.5 End points

E.5.1

Primary end point(s)

Progression free survival (PFS)

Progressions fri overlevelse (PFS)

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months after the inclusion of the last patient

6 måneder efter inklusionen af den sidste patient

E.5.2

Secondary end point(s)

1. Grade and number of adverse events
2. Overall survival after 1 year
3. Overall survival after 5 years
4.Evaluation of possible prognostic and predictive biomarkers

1. Opgørelse af bivirkninger (grad og hyppighed)
2. Overlevelsen efter 1 år
3. Overlevelsen efter 5 år
3.Evaluere potentielle prognostiske og prediktive biomarkører

E.5.2.1

Timepoint(s) of evaluation of this end point

The primary analysis of efficacy and safety parameters will be performed when all 50 patients enrolled in the study have either died, withdrawn consent or have been followed for at least 6 months.
The final analysis of this study will be performed when all patients enrolled have either died, withdrawn consent, are lost to follow up or have been followed up for up to 5 years.

Den primære analyse vil blive foretaget når samtlige inkluderede patienter enten er døde,har tilbagetrukket samtykke eller er fulgt i mindst 6 måneder.
Den endelige analyse vil blive foretaget når samtlige inkluderede patienter enten er døde,har tilbagetrukket samtykke eller er fulgt i op til 5 år.

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

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

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)

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

The study will end when all patients enrolled have developed progressive disease (as per RECIST v1.1), died, withdrawn consent, are lost to follow up, start another anti-cancer therapy, the end of follow-up or the study is terminated by the Sponsor.
Patients will be followed for up to 10 years.

Studiet afsluttes når alle patienter inkluderet har fået konstateret sygdoms progression (defineret i henhold til RECIST v1.1), er døde, har tilbagetrukket deres samtykke, manglende follow-up, påbegynt anden anti-cancer behandling, follow-up er over eller studiet er afsluttet af Sponsor.Patienterne vil blive fulgt i op til 10 år.

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

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:

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

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

Not different from normal treatment of this group of patients

Samme behandling som andre patienter med udbredt modermærkekræft

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	GCP-Unit, Institute of Clinical Medicine
G.4.3.4	Network Country	Denmark

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-07-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-06-19

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2015-02-20

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