Clinical Trials Register

Summary
EudraCT Number:	2011-005718-12
Sponsor's Protocol Code Number:	AP26113-11-101
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:	2012-03-28
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

2011-005718-12

A.3

Full title of the trial

A Phase 1/2 Study of the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral ALK/EGFR Inhibitor AP26113

Estudio en fase 1/2 sobre la seguridad, tolerabilidad, farmacocinética y actividad antitumoral preliminar de AP26113, un inhibidor de ALK/EGFR administrado por vía oral

A.3.1

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

A Phase 1/2 Study of the Oral ALK/EGFR Inhibitor AP26113

En fase 1/2 sobre un inhibidor de ALK/EGFR administrado por vía oral

A.4.1

Sponsor's protocol code number

AP26113-11-101

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01449461

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	ARIAD Pharmaceuticals, 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	ARIAD Pharmaceuticals, 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	Nexus Oncology Ltd.
B.5.2	Functional name of contact point	AP26113-11-101 Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Roslin Biocentre
B.5.3.2	Town/ city	Roslin, Midlothian
B.5.3.3	Post code	EH25 9TT
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	44131200 6320
B.5.5	Fax number	44131200 6322
B.5.6	E-mail	contact@nexusoncology.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	AP26113
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.3.9.2	Current sponsor code	AP26113
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	30
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

Dose Escalation Phase: Histologically confirmed advanced malignancies. All histologies except leukaemia.
Dose Expansion Phase: Non-small cell lung cancer (NSCLC)

Fase de aumento escalonado de dosis: Neoplasias malignas avanzadas, confirmadas histológicamente. Todas las histologías, excepto leucemia.
Fase de ampliación de dosis: Cáncer pulmonar no microcítico (CPNM)

E.1.1.1

Medical condition in easily understood language

advanced malignancies
non-small cell lung cancer (NSCLC)

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	14.1
E.1.2	Level	HLT
E.1.2	Classification code	10029105
E.1.2	Term	Neoplasms malignant site unspecified NEC
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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10048683
E.1.2	Term	Advanced cancer
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	14.1
E.1.2	Level	SOC
E.1.2	Classification code	10029104
E.1.2	Term	Neoplasms benign, malignant and unspecified (incl cysts and polyps)
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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10028997
E.1.2	Term	Neoplasm 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	14.1
E.1.2	Level	HLGT
E.1.2	Classification code	10027655
E.1.2	Term	Miscellaneous and site unspecified neoplasms malignant and unspecified
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

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the safety profile of orally administered AP26113 including identification of the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs).

Determinar el perfil de seguridad de AP26113 administrado por vía
oral, incluyendo la identificación de la dosis máxima tolerada
(DMT) y la toxicidad limitante de dosis (TLD).

E.2.2

Secondary objectives of the trial

1.To determine the recommended phase 2 dose (RP2D) of orally administered AP26113.
2.To examine the pharmacokinetic (PK) profile of AP26113.
3.To describe the preliminary anti-tumor activity of AP26113 in NSCLC with ALK gene rearrangement or mutant EGFR activity, and other cancers with abnormal targets.
4.To perform exploratory analysis including molecular assessments.

1. Determinar la DRF2 de AP26113 administrado por vía oral.
2. Evaluar el perfil farmacocinético (FC) de AP26113.
3. Describir la actividad antitumoral preliminar de AP26113 en el
CPNM con reordenación del gen ALK o EGFR mutado, así como en
otras neoplasias malignas con dianas alteradas.
4. Realizar un análisis exploratorio que incluya evaluaciones
moleculares.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

All patients must meet all the following eligibility criteria for study entry.
1. All patients must have tumor tissue available for analysis. If sufficient tissue is not available, patients must undergo a biopsy to obtain adequate samples. Patients with less tissue than required can be enrolled only with prior approval from the Sponsor.
In the expansion cohorts, for which failure of prior therapy is specified (expansion cohorts 2 and 3), tumor tissue must be obtained following failure of the prior therapy.
2. Must have measurable disease by RECIST (version 1.1).
3. Male or female patients >= 18 years old.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
5. Minimum life expectancy of 3 months or more.
6. Adequate renal and hepatic function as defined by the following criteria:
i. Total serum bilirubin <= 2 x upper limit of normal (ULN);
ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
<= 2.5 x ULN (or <= 5 x ULN if liver function abnormalities are due to underlying malignancy);
iii. Serum creatinine < 2 x ULN;
iv. Serum albumin >= 2 g/dL.
7. Adequate bone marrow function as defined by the following criteria:
i. Absolute neutrophil count (ANC) >= 1500/μL;
ii. Platelets >=75,000/μL;
iii. Hemoglobin >= 9.0 g/dL.
8. Normal QT interval on screening electrocardiogram (ECG) evaluation, defined as QTcF of <= 450 ms in males or <= 470 ms in females.
9. For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment.
10. Female and male patients who are of childbearing potential must agree to use an effective form of contraception with their sexual partners throughout study participation.
11. Signed and dated informed consent indicating that the patient has been informed of all pertinent aspects of the study.
12. Willingness and ability to comply with scheduled visits and study procedures.

Todos los pacientes deberán reunir los siguientes criterios de elegibilidad para poder ser incluidos en el estudio.
1. Todos los pacientes deberán tener tejido tumoral disponible para su análisis. Los pacientes que no dispongan de tejido suficiente deberán hacerse una biopsia para obtener muestras adecuadas.
En las cohortes de ampliación, en las que se especifica el fracaso de la terapia previa (cohortes de ampliación 2 y 3), deberá obtenerse tejido tumoral después
del fracaso de la terapia previa.
2. Deberán presentar enfermedad evaluable según los criterios RECIST (versión 1.1).
3. Pacientes (hombres y mujeres) >=18 años de edad.
4. Grado de actividad ECOG (Eastern Cooperative Oncology Group) de 0 a 2.
5. Esperanza de vida mínima de 3 meses o más.
6. Función hepática y renal adecuada, definida según los siguientes criterios:
i. Bilirrubina total en suero <=2 x límite superior de la normalidad (LSN).
ii. Alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST) <=2,5 x LSN (o <=5 x LSN si las alteraciones de la función hepática se deben a la neoplasia maligna subyacente).
iii. Creatinina sérica <2 x LSN.
iv. Albúmina sérica >=2 g/dL.
7. Función adecuada de la médula ósea, definida según los siguientes criterios:
i. Recuento absoluto de neutrófilos (RAN) >=1500/μL.
ii. Plaquetas >=75 000/μL.
iii. Hemoglobina >=9,0 g/dL.
8. Intervalo QT normal en el electrocardiograma (ECG) de selección, definido como un intervalo QTcF <=450 mseg en hombres o <=470 mseg en mujeres.
9. En el caso de las mujeres con posibilidad de quedarse
embarazadas, deberá realizarse una prueba de embarazo que
resulte negativa antes de la inclusión en el estudio.
10. A lo largo de todo el estudio, las mujeres y hombres potencialmente fértiles deberán utilizar un método anticonceptivo eficaz con sus parejas.
11. Consentimiento informado firmado y fechado, que indique que el paciente ha sido informado de todos los aspectos relevantes del estudio.
12. Voluntad y capacidad para cumplir con las visitas programadas y los procedimientos del estudio.

E.4

Principal exclusion criteria

Patients are not eligible for participation in the study if they meet or have any of the following exclusion criteria:
1. Received an investigational agent within 14 days prior to initiating AP26113.
2. Received systemic anticancer therapy or radiation therapy within 14 days prior to initiating AP26113
a. Except that for cohorts 3 and 4, EGFR TKI therapy is allowed up to 72 hours
prior to initiating AP26113.
3. Major surgery within 28 days prior to initiating AP26113.
4. Active metastases in the brain or central nervous system (CNS). If present, metastases must be stable for at least 8 weeks as documented by magnetic resonance imaging (MRI) or, in the case of meningeal involvement, by a negative lumbar puncture prior to study entry.
5. Significant uncontrolled or active cardiovascular disease, specifically including, but not restricted to:
a. Myocardial infarction, unstable angina and/or congestive heart failure within
3 months prior to first dose of AP26113;
b. History of clinically significant (as determined by the treating physician) atrial
arrhythmia or any ventricular arrhythmia.
6. Uncontrolled hypertension (Diastolic blood pressure [BP] > 100 mm Hg; Systolic
> 150 mm Hg).
7. Prolonged QTcF interval, or being treated with medications known to cause Torsades
de Pointes (refer to Attachment 4).
8. Ongoing or active infection. The requirement for IV antibiotics is considered active infection.
9. Known history of human immunodeficiency virus (HIV). Testing is not required in the absence of history.
10. Pregnant or breastfeeding.
11. Malabsorption syndrome or other gastrointestinal illness that could affect oral
absorption of AP26113.
12. Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the safety of the drug.

No serán aptos para participar en el estudio los pacientes que cumplan o presenten cualquiera de los siguientes criterios de exclusión:
1. Haber recibido un fármaco en investigación en los 14 días previos al inicio de AP26113.
2. Haber recibido terapia antineoplásica sistémica o radioterapia en los 14 días previos al inicio de AP26113.
a. A excepción de las cohortes 3 y 4, la terapia con TKI de EGFR está permitida hasta 72 horas antes del inicio de AP26113.
3. Cirugía mayor en los 28 días previos al inicio de AP26113.
4. Metástasis activas en el cerebro o el sistema nervioso central (SNC). Si hubiese metástasis presentes, deberán estar estables durante al menos 8 semanas, documentándolo mediante resonancia magnética (RM) o, en caso de afectación meníngea, mediante una punción lumbar negativa antes de la
inclusión en el estudio.
5. Enfermedad cardiovascular importante, activa o no controlada, incluyendo específicamente (entre otras):
a. Infarto de miocardio, angina inestable y/o insuficiencia cardiaca congestiva en los 3 meses previos a la primera dosis de AP26113.
b. Historial de arritmia ventricular clínicamente significativa (según determinación del médico responsable del tratamiento) o cualquier arritmia
ventricular.
6. Hipertensión no controlada (tensión arterial [TA] diastólica
>100 mm Hg y sistólica >150 mm Hg).
7. Intervalo QTcF prolongado o tratamiento con medicamentos que se sabe causan Torsades de Pointes (véase el Anexo 4).
8. Infección activa o continuada. La necesidad de antibióticos por vía intravenosa (i.v.) se considera infección activa.
9. Historial médico conocido de infección por el virus de la inmunodeficiencia humana (VIH). Si no aparece en la historia clínica no es necesario hacer análisis.
10. Embarazo o lactancia.
11. Síndrome de malabsorción u otra patología gastrointestinal que pueda afectar a la absorción oral de AP26113.
12. Cualquier patología o enfermedad que, en opinión del investigador, pueda comprometer la seguridad del paciente o interferir con la evaluación de seguridad del fármaco.

E.5 End points

E.5.1

Primary end point(s)

Primary Endpoint for Dose Escalation:
1. RP2D of orally administered AP26113.

Expansion Cohorts
Primary Endpoint:
1. Overall response rate (using Response Evaluation Criteria in Solid Tumors [RECIST]).

Componente de aumento escalonado de dosis
Criterio principal de valoración
1. DRF2 de AP26113 administrado por vía oral.

Cohortes de ampliación
Criterio principal de valoración:
1. Tasa de respuesta global (utilizando los criterios RECIST de
evaluación de la respuesta de los tumores sólidos).

E.5.1.1

Timepoint(s) of evaluation of this end point

RP2D: Not applicable for individual patients
Overall response rate: throughout course of treatment

DRF2: no aplica para pacientes a nivel individual.
Tasa de respuesta global: a lo largo del tratamiento.

E.5.2

Secondary end point(s)

Secondary Endpoints for Dose Escalation:
1. MTD of orally administered AP26113.
2. Safety, tolerability and DLTs of AP26113.
3. Plasma PK parameters of single-dose and steady state AP26113.

Secondary Endpoints for Expansion Cohorts:
1. Safety and tolerability of AP26113.
2. Plasma PK parameters.
3. Efficacy assessments include: best target lesion response; progression free survival (PFS); time to progression (TTP); time to treatment failure in patients who remain on study after RECIST progression, but who continue to benefit according to the treating investigator. Overall survival (OS) will also be measured for up to 2 years following the first dose of AP26113.

Componente de aumento escalonado de dosis
Criterios secundarios de valoración:
1. DMT de AP26113 administrado por vía oral.
2. Seguridad, tolerabilidad y TLD de AP26113.
3. Parámetros FC en plasma de AP26113 en dosis única y en equilibrio.

Cohortes de ampliación
Criterios secundarios de valoración
1. Seguridad y tolerabilidad de AP26113.
2. Parámetros FC en plasma.
3. La evaluación de eficacia: mejor respuesta de la lesión diana; supervivencia sin progresión (SSP); tiempo hasta la progresión (TP); tiempo hasta el fracaso del tratamiento en pacientes que continúan en el estudio tras la progresión
RECIST, pero que siguen beneficiándose según el investigador responsable del tratamiento. También se medirá la supervivencia global (SG) durante los 2 años siguientes a la primera dosis de AP26113.

E.5.2.1

Timepoint(s) of evaluation of this end point

MTD: Not applicable for individual patients
Safety, tolerability and DLTs: throughout course of treatment
Plasma PK: Cycle 1: Days 1, 2, 8, 15, 22; Cycle 2: Days 1, 2, 3
Efficacy assessments: throughout course of treatment
Overall survival: monitored for up to 2 years following first dose AP26113

DMT: no aplica para pacientes a nivel individual.
Seguridad, tolerabilidad y TLD: a lo largo del tratamiento.
FC en plasma: Ciclo 1: Días 1, 2, 8, 15, 22; Ciclo 2: Días 1, 2, 3.
Evaluaciones de eficacia: a lo largo del tratamiento.
Supervivencia global: se medirá durante los 2 años siguientes a la primera dosis de AP26113.

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

Yes

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)

Yes

E.7.1.1

First administration to humans

Yes

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