Clinical Trials Register

Summary
EudraCT Number:	2013-001986-18
Sponsor's Protocol Code Number:	CMEK162X2116
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-09-16
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

Spain - AEMPS

A.2

EudraCT number

2013-001986-18

A.3

Full title of the trial

A phase Ib/II, open-label, multi-center, dose escalation study of MEK162 in combination with panitumumab in adult patients with mutant RAS or wild-type RAS metastatic colorectal cancer

Estudio de fase Ib/ll, multicéntrico, abierto, de escalada de dosis de MEK162 en combinación con panitumumab en pacientes adultos con cáncer colorrectal metastásico con RAS mutado o no mutado

A.3.1

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

Phase Ib/II study of efficacy and safety of MEK162 plus panitumumab in adult metastatic colorectal cancer patients with mutant or wild-type
RAS tumors

Estudio fase Ib/II de la eficacia y seguridad de MEK162 y panitumumab en pacientes adultos con cáncer colorrectal metastásico con tumores con RAS mutado o no mutado

A.4.1

Sponsor's protocol code number

CMEK162X2116

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.
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.
B.5.2	Functional name of contact point	Margaret Vargo
B.5.3	Address:
B.5.3.1	Street Address	3200 Walnut Street
B.5.3.2	Town/ city	Boulder
B.5.3.3	Post code	08301
B.5.3.4	Country	United States
B.5.4	Telephone number	13033861485
B.5.5	Fax number	13033861252
B.5.6	E-mail	margie.vargo@arraybiopharma.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.3.8	INN - Proposed INN	MEK162
D.3.9.1	CAS number	606143-89-9
D.3.9.2	Current sponsor code	MEK162
D.3.9.3	Other descriptive name	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	Yes
D.2.1.1.1	Trade name	Vectibix
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe B.V
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	panitumumab
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	PANITUMUMAB
D.3.9.1	CAS number	339177-26-3
D.3.9.2	Current sponsor code	PANITUMUMAB
D.3.9.3	Other descriptive name	PANITUMUMAB
D.3.9.4	EV Substance Code	SUB25390
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	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)	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	Yes
D.3.11.13.1	Other medicinal product type	nonchimeric, fully human, IgG2 monoclonal antibody

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

Mutant RAS or wild-type (WT) RAS metastatic colorectal cancer

Cáncer colorrectal metastásico con RAS mutado o no mutado

E.1.1.1

Medical condition in easily understood language

Mutant RAS or wild-type (WT) RAS metastatic colorectal cancer

Cáncer colorrectal metastásico con RAS mutado o no mutado

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	PT
E.1.2	Classification code	10052358
E.1.2	Term	Colorectal cancer metastatic
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10010023
E.1.2	Term	Colorectal neoplasms malignant
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10010030
E.1.2	Term	Colorectal cancer recurrent
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10061451
E.1.2	Term	Colorectal cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Phase Ib: To estimate the MTD and/or RP2D of MEK162 in combination with panitumumab
Phase II: To assess clinical efficacy of the MEK162 and panitumumab combination

Fase Ib: determinar la DMT y/o DRF2 de MEK162 en combinación con panitumumab en pacientes con cáncer colorrectal metastásico con RAS mutado o no mutado.
Fase II: evaluar la eficacia clínica de la combinación de MEK162 y panitumumab en los 4 brazos de la fase II.

E.2.2

Secondary objectives of the trial

Phase Ib and Phase II
To characterize the safety and tolerability of the MEK162 and panitumumab combination
Phase Ib only
To assess preliminary anti-tumor activity of the MEK162 and panitumumab combination
Phase II only
To assess additional anti-tumor activity of the MEK162 and panitumumab combination

Fase Ib + II: caracterizar la seguridad y la tolerabilidad de la combinación de MEK162 y panitumumab.
Fase Ib: evaluar la actividad antitumoral clínica preliminar de la combinación de MEK162 y panitumumab.
Fase II: continuar evaluando la eficacia clínica de la combinación de MEK162 y panitumumab en los 4 brazos de la fase II.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age > o = 18 years
2. Histological or cytological confirmation of mCRC
3. For the dose escalation (Phase Ib): Progression on or following standard therapy or for whom no standard therapy exists. See protocol for complete details
4. Phase Ib and Phase II: Written documentation of WT RAS or somatic mutation in exon 2 (codons 12/13), 3 (codons 59/61) or 4 (codons 117/146) in either KRAS or NRAS in medical history.
5. Evidence of measurable disease, as determined by RECIST v1.1.
6. Life expectancy > o = 3 months.
Other protocol-defined inclusion criteria may apply

1. Pacientes > o = 18 años de edad.
2. Confirmación histológica o citológica de cáncer colorrectal metastásico
3. Para la escalada de dosis (Fase Ib): Progresión durante o después de tratamiento estándar o para quienes no exista ningún tratamiento estándar. Ver protocolo para más información.
4. Fase Ib y Fase II: documentación escrita sobre RAS no mutado o mutación somática en el exón 2 (codones 12/13), 3 (codones 59/61) o 4 (codones 117/146) en KRAS o NRAS en la historia clínica.
5. Evidencia de enfermedad medible, según RECIST v1.1.
6. Esperanza de vida > o = 3 meses.
Otros criterios de inclusión aplicables definidos por protocolo.

E.4

Principal exclusion criteria

1.Phase II arms 1 and 4 only: previous treatment with cetuximab, panitumumab, and/or other EGFR inhibitors. For arms 2 and 3: EGFR tyrosine kinase inhibitor therapy.
2.Previous treatment with MEK-inhibitors - certain exceptions. See protocol
3.Patients with known history of severe infusion reactions to monoclonal antibodies.
4.Known hypersensitivity and/or contraindication to any of the study medications or their excipients
5.Symptomatic or untreated leptomeningeal disease.
6.Symptomatic brain metastasis.
7.History or current evidence of retinal disease or ophthalmopathy
8.History of keratitis or ulcerative keratitis.
9.Known acute or chronic pancreatitis.
10.Clinically significant cardiac disease - see protocol
11. Not adequate hematologic, renal and hepatic function
12.Impairment of gastrointestinal function or GI disease that may significantly alter the absorption of oral MEK162
13.Previous or concurrent malignancy - with exceptions - see protocol
14.History of thromboembolic or cerebrovascular events within the last 6 months
15.Patients who have received radiation therapy , chemotherapy, biological therapy within ? 4 weeks or who have been treated with continuous or intermittent small molecule therapeutics or investigational agents within 5 half-lives of the agent - See protocol
16.Patients who have undergone any major surgery within the last 2 weeks prior to starting study drug or who would not have fully recovered from previous surgery.
17.Known human immunodeficiency virus (HIV) infection.
18.Pregnant or nursing (lactating) women
Other protocol-defined exclusion criteria may apply

1. Solo los brazos 1 y 4 de la fase II: tratamiento previo con cetuximab, panitumumab y/u otros inhibidores de EGFR. En los brazos 2 y 3: tratamiento con inhibidores de la tirosina quinasa EGFR.
2. Tratamiento previo con inhibidores de MEK - pueden realizarse excepciones. Ver protocolo
3. Pacientes con una historia conocida de reacciones graves a la perfusión de anticuerpos monoclonales.
4. Hipersensibilidad conocida y/o contraindicación a cualquier fármaco del estudio o sus excipientes
5. Enfermedad leptomeníngea sintomática o no tratada
6. Metástasis cerebrales sintomáticas
7. Antecedentes o evidencia actual de enfermedad retiniana u oftalmopatía
8. Antecedentes de queratitis o queratitis ulcerosa
9. Pancreatitis aguda o crónica conocida
10. Enfermedad cardíaca clínicamente significativa - Ver protocolo
11. Función hematológica, renal y hepática inadecuada
12. Alteraciones de la función gastrointestinal (GI) o enfermedad GI que pudiesen alterar significativamente la absorción de MEK162 oral
13. Tumor maligno previo o concurrente - con excepciones - ver protocolo
14. Antecedentes de acontecimientos tromboembólicos o cerebrovasculares durante los últimos 6 meses
15. Pacientes que hayan recibido radioterapia, quimioterapia, terapia biológica durante < o = 4 semanas anteriores o que hayan recibido terapia continua o intermitente con moléculas pequeñas, o cualquier otro fármaco de investigación dentro de un periodo de tiempo de 5 semividas del fármaco - ver protocolo
16. Pacientes sometidos a una cirugía mayor durante las 2 semanas anteriores al inicio del fármaco del estudio o que no se hayan recuperado completamente de una cirugía anterior.
17. Infección conocida del virus de la inmunodeficiencia humana (VIH).
18. Mujeres embarazadas o en período de lactancia
Otros criterios de exclusión aplicables definidos por protocolo.

E.5 End points

E.5.1

Primary end point(s)

Phase Ib: Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1
Phase II: Overall response rate (ORR) as per RECIST v1.1

Fase Ib: Incidencia de las toxicidades limitantes de dosis (TLD) en el ciclo 1.
Fase II: Tasa de respuesta global (TRG) según RECIST v1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

DLTs- Approximately 3-6 months
ORR- Approximately 12 months

TLDs- 3-6 meses aproximadamente
TRG- 12 meses aproximadamente

E.5.2

Secondary end point(s)

Phase Ib: ORR, Progression-free survival, (PFS), duration of response (DOR), disease control rate
(DCR) as per RECIST v1.1
Phase II: PFS, DOR, DCR as per RECIST v1.1 and OS
Phase Ib and Phase II: Frequency and severity of Adverse Events (AEs), SAEs, changes in laboratory
values, vital signs, and electrocardiograms

Fase Ib: TRG, supervivencia libre de progresión (SLP), duración de la respuesta (DR), tasa de control de la enfermedad (TCE) según RECIST v1.1.
Fase II: SLP, DR, TCE según RECIST v1.1 y SG.
Fase Ib y Fase II: Frecuencia y gravedad de los acontecimientos adversos (AAs) y AAGs, cambios en los valores de laboratorio, constantes vitales y electrocardiogramas.

E.5.2.1

Timepoint(s) of evaluation of this end point

Approximately 12-18 months

12-18 meses aproximadamente

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

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Dose-finding, Dose-escalation

De búsqueda de dosis, dosis-escalada

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

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

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

Belgium

Canada

France

Germany

Italy

Netherlands

Spain

United States

E.8.7

Trial has a data monitoring committee

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 will be upon Study Evaluation Completion (SEC) of the last patient treated.

El fin del estudio se producirá tras la finalización de la evaluación del estudio (FEE) del último paciente tratado.

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

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

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

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)

None

Ninguno

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

2013-11-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-10-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-01-25

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IMP with orphan designation in the indication
Orphan Designation Number:
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