Clinical Trials Register

Summary
EudraCT Number:	2013-001176-38
Sponsor's Protocol Code Number:	CMEK162B2301
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2014-05-15
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

Portugal - INFARMED

A.2

EudraCT number

2013-001176-38

A.3

Full title of the trial

A 2-part phase III randomized, open label, multicenter study of LGX818
plus MEK162 versus vemurafenib and LGX818 monotherapy in patients
with unresectable or metastatic BRAF V600 mutant melanoma

A.3.1

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

A study comparing combination of LGX818 plus MEK162 vs. vemurafenib,
and LGX818 plus MEK162 vs. LGX818 in BRAF mutant melanoma.

A.3.2

Name or abbreviated title of the trial where available

COLUMBUS

A.4.1

Sponsor's protocol code number

CMEK162B2301

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	Array BioPharma Inc. (a wholly owned subsidiary of Pfizer Inc.)
B.1.3.4	Country	United States
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	Array BioPharma Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Array BioPharma Inc. (a wholly owned subsidiary of Pfizer Inc.)
B.5.2	Functional name of contact point	Clinical Trials.gov Call Centre
B.5.3	Address:
B.5.3.1	Street Address	235 East 42nd Street
B.5.3.2	Town/ city	New York
B.5.3.3	Post code	10017
B.5.3.4	Country	United States
B.5.4	Telephone number	+1800718 1021
B.5.6	E-mail	ClinicalTrials.gov_Inquiries@pfizer.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.3.2	Product code	MEK162
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.3.9.1	CAS number	606143-89-9
D.3.9.2	Current sponsor code	MEK162
D.3.9.4	EV Substance Code	SUB31901
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	15
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	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.3.2	Product code	LGX818
D.3.4	Pharmaceutical form	Capsule
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.3.9.2	Current sponsor code	LGX818
D.3.9.4	EV Substance Code	SUB32790
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	50
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: 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	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.3.2	Product code	LGX818
D.3.4	Pharmaceutical form	Capsule
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.3.9.2	Current sponsor code	LGX818
D.3.9.4	EV Substance Code	SUB32790
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	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: 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	Zelboraf
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
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	vemurafenib
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.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

unresectable or metastatic BRAF V600 mutant melanoma

E.1.1.1

Medical condition in easily understood language

melanoma

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10053571
E.1.2	Term	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 determine whether treatment with Combo 450 (LGX818 450mg QD
plus MEK162 45mg BID) prolongs progression free survival (PFS)
compared with vemurafenib in patients with BRAF V600 mutant locally
advanced unresectable or metastatic melanoma.

E.2.2

Secondary objectives of the trial

Key Part1
1) Determine the contribution of MEK162 to the Combo using PFS
Combo450 vs. LGX818

Key Part2
2) Further quantify the contribution of MEK162 to the Combo using PFS
Combo300 vs. LGX818
Other part specific
-Compare / estimate the effect of (3) Combo450 vs. vemurafenib / (4)
Combo450 vs. LGX818 in overall survival (OS) in Part1
-Estimate the safety and tolerability of (5) Combo450 and LGX818 in
part1, (6) Combo300 vs. LGX818, (7) Combo300 vs. Combo450 in Part2
-Estimate the effect of (8) Combo300 vs. LGX818 in OS in Part2
-Estimate the effect in PFS and OS of (9) Combo300 vs. vemurafenib and
(10) Combo300 vs. Combo450 in Part2

Other Part1 and 2
-Estimate (11) the effect of LGX818 vs. vemurafenib in PFS and OS
-Assess (12) objective response rate, (14) disease control rate, (15)
duration of response
-Describe (13) time to objective response
-Compare (16) patient-reported outcomes, (17) ECOG PS
-Characterize (18) pharmacokinetics of LGX818 and MEK162

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma (AJCC Stage IIIB, IIIC, or IV)
• Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to randomization
• Naïve untreated patients or patients who have progressed on or after prior first-line immunotherapy for unresectable locally advanced or metastatic melanoma; prior adjuvant therapy is permitted (e.g. IFN, IL-2 therapy, any other immunotherapy or radiotherapy), except the administration of BRAF or MEK inhibitors.
• Evidence of at least one measurable lesion as detected by radiological or photographic methods
• ECOG performance status of 0 or 1
• Adequate bone marrow, organ function, cardiac and laboratory parameters
• Normal functioning of daily living activities

Other protocol-defined inclusion criteria may apply

E.4

Principal exclusion criteria

• Any untreated central nervous system (CNS lesion)
• Mucosal or uveal melanoma
• History of leptomeningeal metastases
• History of or current evidence of retinal vein occlusion (RVO)
• Patients with washout period < 6 weeks from the last dose of ipilimumab or other immunotherapy.
• Any previous systemic chemotherapy treatment, extensive radiotherapy or investigational agent other than immunotherapy, or patients who have received more than one line of immunotherapy for locally advanced unresectable or metastatic melanoma.
• History of Gilbert's syndrome
• Prior therapy with a BRAF inhibitor and/or a MEK- inhibitor
• Impaired cardiovascular function or clinically significant cardiovascular diseases
• Uncontrolled arterial hypertension despite medical treatment
• HIV positive or active Hepatitis B, and/or active Hepatitis C
• Impairment of gastrointestinal function
• Patients with neuromuscular disorders that are associated with elevated CK.
• Pregnant or nursing (lactating) women
•Patients taking non-topical medication known to be a strong inhibitor of CYP3A4
• Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study

Other protocol-defined exclusion criteria may apply

E.5 End points

E.5.1

Primary end point(s)

Progression free survival:
PFS is defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause, whichever occurs first. PFS will be determined based on tumor assessment (RECIST version 1.1 criteria) as per Blinded Independent Review Committee (BIRC) and survival information. The local Investigator's assessments will be used as supportive analyses.

E.5.1.1

Timepoint(s) of evaluation of this end point

Approximately 2 years

E.5.2

Secondary end point(s)

-Overall survival: time from the date of randomization to date of death
due to any cause
-Safety and tolerability: Adverse events and serious adverse events,
changes in laboratory values, vital signs, ECGs, MUGA/echocardiogram
and assessment of physical, dermatological and ocular examinations
graded according to the NCI CTCAE v4.03
-Objective response rate: proportion of patient with a best overall
response of complete response (CR) or partial response (PR). ORR will
be calculated for confirmed and unconfirmed responses separately.
-Time to objective response: the time from date of randomization until
first documented CR or PR.
-Disease control rate: proportion of patient with a best overall response
of CR, PR or stable disease (SD)
-Duration of response: time from the date of first documented CR or PR
to the first documented progression or death due to underlying cancer
-Time to definitive 10% deterioration in the FACT-M melanoma subscale
and global health status score of the EORTC QLQ-C30.
-Change from baseline in the FACT-M melanoma subscale, EQ- 5D-5L,
global health status score of the EORTC QLQ-C30 other EORTC QLQ-C30
subscales.
-Time to definitive 1 point deterioration in ECOG PS Change from
baseline in ECOG PS
-Plasma concentration-profiles of LGX818 and MEK162 and model based
PK parameters

E.5.2.1

Timepoint(s) of evaluation of this end point

Key Part1
1) about 2 years
Key Part2
2) about 3 years
Other part specific
-(3), (4) about 5.5 years
-(5)about 2 years
-(6), (7) about 3 years
-(8) about 5.5 years
-(9) about 3 for PFS and 5.5 years for OS
-(10) about 3 for PFS and 5.5 years for OS
Other Part 1 and 2
-(11) about 2, 3 and 5 years
-(12), (13), (14), (15), (16), (17) about 2 (for Combo450, LGX818 and
vemurafenib evaluation) and 3 years (for Combo300 evaluation)
-(18) about 2 (for Combo450 and LGX818 evaluation) and 3 years (for
Combo300 evaluation)

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

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

Yes

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

124

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

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

China

Colombia

Israel

Japan

Korea, Republic of

Russian Federation

Singapore

South Africa

Turkey

United States

France

Germany

Greece

Hungary

Italy

Netherlands

Norway

Poland

Portugal

Slovakia

Spain

Sweden

Switzerland

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

Part 1 and Part 2 of the study will each remain open to collect
additional survival and safety data until all patients in the given study
part have permanently discontinued study treatment and 80% of
randomized patients in the study part have died, withdrawn consent for
survival follow-up or are lost to follow-up. As a result, Part 1 and Part 2
of the study may end at different points in time.

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:

675

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

225

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

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

411

F.4.2.2

In the whole clinical trial

900

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)

At the end of the study, access to Combo 450, Combo 300 and/or
LGX818 treatment will be made available to patients who continue to
derive benefit from Combo 450, Combo 300 and/or LGX818 study
treatment.

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

2014-06-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-05-09

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

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