Clinical Trials Register

Summary
EudraCT Number:	2017-000768-13
Sponsor's Protocol Code Number:	TUD-CoBRIM-067
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Restarted
Date on which this record was first entered in the EudraCT database:	2017-08-14
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2017-000768-13

A.3

Full title of the trial

An open-label phase II multicenter study of vemurafenib (Zelboraf®) plus cobimetinib (Cotellic®) after radiosurgery in patients with active BRAF-V600-mutant melanoma brain metastases

A.3.1

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

An open-label phase II multicenter study of vemurafenib (Zelboraf®) plus cobimetinib (Cotellic®) after radiosurgery in patients with active BRAF-V600-mutant melanoma brain metastases

Multizentrische Phase II-Studie zu Vemurafenib plus Cobimetinib nach Strahlenchirurgie bei Melanom-Patienten mit BRAF-V600-Mutation und aktiven Hirnmetastasen

A.3.2

Name or abbreviated title of the trial where available

RadioCoBRIM

A.4.1

Sponsor's protocol code number

TUD-CoBRIM-067

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	Technische Universität Dresden
B.1.3.4	Country	Germany
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	Roche Pharma AG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Technische Universität Dresden
B.5.2	Functional name of contact point	KKS Dresden / Julia Kalinka
B.5.3	Address:
B.5.3.1	Street Address	Fetscherstraße 74
B.5.3.2	Town/ city	Dresden
B.5.3.3	Post code	01307
B.5.3.4	Country	Germany
B.5.4	Telephone number	004935145819632
B.5.5	Fax number	00493514585799
B.5.6	E-mail	RadioCoBRIM.KKS@uniklinikum-dresden.de

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 Pharma AG
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	Zelboraf
D.3.4	Pharmaceutical form	Film-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	Cotellic
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Pharma AG
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	Cobimetinib
D.3.4	Pharmaceutical form	Film-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	Cobimetinib-Hemifumarat
D.3.9.3	Other descriptive name	COBIMETINIB HEMIFUMARATE
D.3.9.4	EV Substance Code	SUB168371
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	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

patients with active BRAF-V600-mutant melanoma brain metastases

E.1.1.1

Medical condition in easily understood language

Histologically confirmed metastatic melanoma carrying BRAF V600-mutation

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	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 investigate the Best overall response rate (BORR) in the brain by combination of vemurafenib plus cobimetinib after radiosurgery in patients with melanoma brain metastases

E.2.2

Secondary objectives of the trial

• Extracranial BORR
• BORR calculated for the whole body tumor sites
• Intracranial duration of response
• Extracranial duration of response
• Progression-free survival (PFS)
• Overall survival (OS)
• Safety
• Radiomics features predictive of long-term local control of brain metastases
• Radiomics features predicting treatment-related toxicity, e.g. radionecrosis, hemorrhage, edema.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Immunomonitoring to provide novel insights into the immune modulatory capacity of the combination therapy of vemurafenib and cobimetinib; blood samples will be taken to study a panel of immunomodulatory cells and molecules (e.g. cytokines)

E.3

Principal inclusion criteria

• Signed informed consent
• Female and male patients ≥ 18 years of age
• Histologically confirmed metastatic melanoma (stage IV, per AJCC staging), carrying BRAF V600-mutation
• Performed SRS 14 ±7 days before baseline using a harmonized protocol in patients with at least one measurable intracranial target lesion for which the following criteria are met:
o Previously untreated (Lesions in previously irradiated area should not be selected)
o Largest diameter of ≥ 0.5 but ≤ 4 cm as determined by contrast-enhanced MRI
o ≤ 10 brain metastases
• ECOG performance status 0 - 2
• Life expectancy ≥ 12 weeks
• Adequate bone marrow function as indicated by the following:
o ANC ≥ 1500/µL
o Platelets ≥ 100,000/µL
o Hemoglobin ≥ 9 g/dL
• Adequate renal function, as indicated by creatinine ≤ 1.5 x ULN
• Adequate liver function, as indicated by bilirubin < 1.5 x ULN and AST and ALT < 3 x ULN (documented liver metastases: AST and ALT < 5 x ULN)
• INR in normal range
• Able to swallow pills

E.4

Principal exclusion criteria

• Symptomatic brain metastases requiring immediate local interventions such as neurosurgery or radiosurgery
• Leptomeningeal disease (also synchronous with brain metastases)
• Prior therapy with BRAF or MEK inhibitors within 12 weeks prior to baseline visit (prior therapies for metastatic melanoma including chemo-, cytokine-, immuno-, biological and vaccine-therapy will be allowed). A period of at least 6 weeks must be observed between the last dose of ipilimumab and the first administration of the study treatments. Prior treatment with anti-programmed cell death (PD)-1 or anti-PD ligand 1 (PD-L1) is allowed.
• Prior whole brain irradiation (Patients with prior local therapy of brain metastases are eligible)
• Patients receiving therapeutic steroids are not stable on corticosteroids 2 weeks before SRS
• Active and uncontrolled infection
• Known HIV infection, or active HBV or HCV infection
o Active HBV infection (chronic and acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at screening (past or resolved HBV infection, defined as negative HBsAg test and a positive total hepatitis B core antibody test at screening, are eligible)
o Active HCV infection, defined as positive HCV antibody test and positive HCV RNA test at screening
• Intracranial radiation therapy within 14 days prior to SRS
• Extracranial radiation therapy within the last 14 days prior to baseline visit
• Treatment with strong CYP3A4/5 inhibitors (e.g. ketoconazole) and inducers (e.g. phenytoin, carbamazepine). (anticonvulsant levetiracetam is allowed; patient should be stable on levetiracetam for 2 weeks)
• Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI v4.0) [NCI, 2009] Grade 2 or higher from previous anti-cancer therapy, except alopecia.
• Conditions that will interfere significantly with the absorption of drugs (e.g. Colitis ulcerosa)
• Inability to undergo MRI secondary to:
o Metal
o Claustrophobia
o Gadolinium contrast allergy
• Previous malignancies active within the last 3 years, with the exception of locally curable cancers that have been treated to complete remission or untreated stage I chronic lymphoid leukemia.
• Unwillingness or inability to comply with study and follow-up procedures
• Known hypersensitivity to any of the excipients of cobimetinib and vemurafinib
• The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment:
o St. John’s wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer)
o Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor)
• Patient is included in another interventional trial
• Use of any investigational or non-registered product within 4 weeks prior to baseline visit
• Pregnant or lactating women
• History, risk factor or retinal pathology that increases the risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR): evidence of retinal pathology that is considered a risk factor for RVO or CSR, or a history of retinal detachment, central serous chorioretinopathy or retinal vein thrombosis. The risk factors for RVO are listed below:
o Uncontrolled glaucoma with intraocular pressures > 21 mm Hg,
o Serum cholesterol ≥ Grade 2 (≥ 7.75 mmol/L),
o Hypertriglyceridemia ≥ Grade 2 (≥ 3.42 mmol/L),
Hyperglycemia (fasting) ≥ Grade 2 (≥ 8.9 mmol/L).
• History of clinically significant cardiac dysfunction including:
o Myocardial infarction,
o Severe/unstable angina pectoris,
o Symptomatic congestive heart failure (NYHA stage ≥ 2),
o cerebrovascular accident or transient ischemic attack within the previous 6 months
o History of congenital long QT syndrome or mean QTcF > 450 msec or uncorrectable electrolyte abnormalities
o Hypertension > Grade 2 not controlled by medications
o Left ventricular ejection fraction (LVEF) < 50%
o Uncontrolled arrhythmias

E.5 End points

E.5.1

Primary end point(s)

Best overall response rate in the brain within two years, defined as the rate of patients with complete response (CR) or partial response (PR)

E.5.1.1

Timepoint(s) of evaluation of this end point

within 2 years of therapy with vemurafenib and cobimetinib, every 6 weeks

E.5.2

Secondary end point(s)

• Extracranial BORR
• BORR calculated for the whole body tumor sites
• Intracranial duration and kind of response
• Extracranial duration and kind of response
• Progression-free survival
• Overall survival
Safety:
• Total adverse events
• Serious adverse events
• ≥ Grade 3 adverse events
• Adverse events of special interest
• Adverse events leading to treatment discontinuation
Further Variables:
• Radiomics features predictive of long-term local control of brain metastases
• Radiomics features predicting treatment-related toxicity, e.g. radionecrosis, hemorrhage, edema.

E.5.2.1

Timepoint(s) of evaluation of this end point

within 2 years of therapy with vemurafenib and cobimetinib, every 3 months

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

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

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

End of Study Visit (2 years after start of treatment )

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.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 end of the study, the local investigator will be responsible for ensuring that consideration has been given for the post-study care of the subject’s medical condition. Due to the brain metastases disease, the patient will be offered a further experimental therapy as no standard treatment is approved at this time.

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

2017-11-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-11-21

P. End of Trial
P.	End of Trial Status	Restarted

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials