Clinical Trials Register

Summary
EudraCT Number:	2014-005350-19
Sponsor's Protocol Code Number:	TTD-14-05
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:	2015-05-08
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

2014-005350-19

A.3

Full title of the trial

A phase I/II study of nab-paclitaxel (Abraxane®) and gemcitabine followed by modified FOLFOX (AG-mFOLFOX) in patients with previously untreated, metastatic pancreatic adenocarcinoma

Estudio fase I / II con nab-paclitaxel (Abraxane®) y gemcitabina seguido de FOLFOX modificado (AG-mFOLFOX) en pacientes con cáncer de páncreas metastásico no tratado

A.3.1

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

Study of Abraxane® and gemcitabine followed by modified FOLFOX in patients with previously untreated, metastatic pancreatic adenocarcinoma

Estudio con Abraxane® y gemcitabina seguido de FOLFOX modificado en pacientes con cáncer de páncreas metastásico no tratado.

A.3.2

Name or abbreviated title of the trial where available

SEQUENCE

A.4.1

Sponsor's protocol code number

TTD-14-05

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	Grupo de Tratamiento de los Tumores Digestivos (TTD)
B.1.3.4	Country	Spain
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	Celgene
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Dynamic Science
B.5.2	Functional name of contact point	Ana Sotés Mendiola
B.5.3	Address:
B.5.3.1	Street Address	C/Sant Antoni María Claret, 434
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08027
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034914561105
B.5.5	Fax number	0034914561126
B.5.6	E-mail	ana.s@dynasolutions.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	Yes
D.2.1.1.1	Trade name	Oxaliplatino
D.2.1.1.2	Name of the Marketing Authorisation holder	Oxaliplatino
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Oxaliplatino
D.3.2	Product code	71555
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	OXALIPLATIN
D.3.9.1	CAS number	61825-94-3
D.3.9.2	Current sponsor code	71555
D.3.9.3	Other descriptive name	Oxalipaltino
D.3.9.4	EV Substance Code	SUB09490MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	85 to 65
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	ABRAXANE 5mg/ml POLVO PARA SUSPENSION PARA PERFUSION
D.2.1.1.2	Name of the Marketing Authorisation holder	Celgene Europe Limited
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	ABRAXANE 5mg/ml POLVO PARA SUSPENSION PARA PERFUSION
D.3.4	Pharmaceutical form	Powder 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	PACLITAXEL
D.3.9.1	CAS number	33069-62-4
D.3.9.2	Current sponsor code	07428001
D.3.9.3	Other descriptive name	Abraxane
D.3.9.4	EV Substance Code	SUB09583MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	125 to 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	Yes
D.3.11.13.1	Other medicinal product type	The IMP contains an excipient of biological origin, albumin, a non-active stabilizing agent. It is derived from human blood subject to approved donor screening and product manufacturing processes
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	5 Fluorouracilo
D.2.1.1.2	Name of the Marketing Authorisation holder	5 fluorouracilo
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	5 Fluorouracilo
D.3.2	Product code	63549
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	flurouracilo
D.3.9.1	CAS number	63549
D.3.9.2	Current sponsor code	63549
D.3.9.3	Other descriptive name	FLUOROURACIL
D.3.9.4	EV Substance Code	SUB07721MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	400 to 200
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	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	GEMCITABINA ACCORD 1500 mg CONCENTRADO PARA SOLUCION PARA PERFUSION
D.2.1.1.2	Name of the Marketing Authorisation holder	GEMCITABINA ACCORD 1500 mg CONCENTRADO PARA SOLUCION PARA PERFUSION
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	GEMCITABINA ACCORD 1500 mg CONCENTRADO PARA SOLUCION PARA PERFUSION
D.3.2	Product code	76157
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	GEMCITABINE
D.3.9.1	CAS number	95058-81-4
D.3.9.2	Current sponsor code	76157
D.3.9.3	Other descriptive name	Gemcitabina
D.3.9.4	EV Substance Code	SUB07892MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1000 to 800
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: 5
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	Acido folínico
D.2.1.1.2	Name of the Marketing Authorisation holder	Acido folínico
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	acido folinico
D.3.2	Product code	70341
D.3.4	Pharmaceutical form	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	acido folinico
D.3.9.1	CAS number	70341
D.3.9.2	Current sponsor code	70341
D.3.9.3	Other descriptive name	FOLINIC ACID
D.3.9.4	EV Substance Code	SUB13910MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	400
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: 6
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	5 Fluorouracilo
D.2.1.1.2	Name of the Marketing Authorisation holder	5 fluorouracilo
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	5 Fluorouracilo
D.3.2	Product code	63549
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	Percutaneous use (Noncurrent) Parenteral use (Noncurrent) Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	flurouracilo
D.3.9.1	CAS number	63549
D.3.9.2	Current sponsor code	63549
D.3.9.3	Other descriptive name	FLUOROURACIL
D.3.9.4	EV Substance Code	SUB07721MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	2400 to 1600
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

Metastatic pancreatic cancer

Cáncer de páncreas metastásico

E.1.1.1

Medical condition in easily understood language

Pancreatic cancer

Cáncer de pancreas

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	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10033605
E.1.2	Term	Pancreatic cancer metastatic
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

Phase I:
- To determine the safety DLT for the AG-mFOLFOX combination.

Phase II:
- Clinical efficacy of AG-mFOLFOX vs AG as measured as % of overall survival al 12 months after treatment initiation.

Ensayo Fase I:
- Determinar la toxicidad limitante de dosis (TLD) para el régimen AG-mFOLFOX.

Ensayo Fase II:
- Eficacia clínica del régimen AG-mFOLFOX vs AG medido como tasa de
supervivencia global a los 12 meses (% SG 12 meses).

E.2.2

Secondary objectives of the trial

Phase I:
- Efficacy of the AG-mFOLFOX in terms of response rate.

Phase II:
- Overall survival at 6 months
- Overall survival at 24 months
- Time to tumor progression
- Progression free survival
- Overall survival
- Objective radiographic response (ORR)
- CA 19-9 biomarker response
- Safety profile of this combination (AG-mFOLFOX)
- Quality of Life of the patients

Ensayo Fase I:
- Eficacia clínica del régimen AG-mFOLFOX en términos de tasa de respuesta.

Ensayo Fase II:
- Tasa de supervivencia global a los 6 meses.
- Tasa de supervivencia global a los 24 meses.
- Tiempo a la progresión (TP).
- Supervivencia libre de progresión (SLP).
- Supervivencia global (SG).
- Respuesta radiográfica objetiva (ORR) según RECIST.
- Respuesta del marcador CA 19-9.
- Perfil de seguridad
- Calidad de vida de los pacientes

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

Biological study to determine possible predictors of
efficacy. Versión 1.0 (20/03/2015).

Estudio biológico para la determinación de posibles factores predictores de
eficacia. Versión 1.0 de fecha 20 de marzo de 2015.

E.3

Principal inclusion criteria

- Histologically and/or cytologically confirmed pancreatic adenocarcinoma
- Stage IV disease (metastatic pancreatic cancer).
- No prior systemic therapy for their diagnosis (except in adjuvant setting with or without radiotherapy during previous six months.
- ECOG performance status of 0-1
- At least 18 years of age
- RECIST versión 1.1. defined measurable disease
- Female patients must be either surgically sterile or postmenopausal, or if of childbearing potential must have
a negative pregnancy test (serum or urine) prior to
enrollment and agree to use effective barrier contraception during the period of therapy. Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study. Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy. The definition of effective contraception will be based on the judgment of the investigator.
- Adequate bone marrow function:
ANC ≥ 1500/uL
Platelet count ≥100,000/uL
Hemoglobin ≥ 9.0 g/dL
- Adequate hepatic function:
Total bilirubin ≤ 1.5 X ULN or until 2mg/dL
AST (SGOT) ≤ 2.5 X ULN ≤ 5 X ULN if liver metastases
ALT (SGPT) ≤ 2.5 X ULN ≤ 5 X ULN if liver metastases
Adequate renal function as determined by either:
- Calculated or measured creatinine clearance ≥ 40 mL/min (for calculated creatinine clearance, Cockroft-Gault equation will be used)
- Ability to understand the nature of this study protocol and give written informed consent.
- Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures

- Confirmación histológica y/o citológica de adenocarcinoma de páncreas.
- Pacientes con adenocarcinoma de páncreas metastásico (estadio IV).
- No haber recibido tratamiento sistémico previo o terapia investigacional para cáncer de páncreas metastásico. Se permite haber recibido tratamiento de quimioterapia adyuvante solo o en combinación con radioterapia al menos 6 meses antes de la inclusión.
- ECOG 0-1
- Edad ≥ 18 años.
- Enfermedad medible siguiendo los criterios RECIST versión 1.1.
- Las pacientes deben estar esterilizadas quirúrgicamente o posmenopáusica, o si está en edad fértil deben tener una prueba negativa de embarazo (suero u orina) antes de la inclusión en el estudio y deben usar anticonceptivos de barrera efectiva o abstinencia durante el período de tratamiento. Los anticonceptivos orales, implantables o inyectables pueden verse afectados por las interacciones del citocromo P450, y por lo tanto no se consideran eficaces para este estudio. Los pacientes varones deben estar esterilizados quirúrgicamente o utilizar un método anticonceptivo eficaz o abstinencia durante el periodo de tratamiento. La definición de un método anticonceptivo eficaz se basará en el criterio del investigador.
- Adecuada función de la médula ósea, según:
Hemoglobina ≥ 9,0 g/dl (pacientes con hemoglobina < 9 g/dl pueden transfundirse antes de la inclusión en el estudio)
Recuento de plaquetas ≥ 100 x 109/L
Recuento absoluto de neutrófilos (RAN) ≥ 1.5x 109/L
- Adecuada función hepática, según:
Bilirrubina sérica ≤ 1.5 X el límite superior de la normalidad (LSN) o hasta 2 mg/dL.
AST (SGOT) ≤ 2.5 X LSN o ≤ 5 X ULN en presencia de metástasis hepáticas.
ALT (SGPT) ≤ 2.5 X LSN o ≤ 5 X ULN en presencia de metástasis hepáticas.
- Adecuada función renal, según:
Aclaramiento de creatinina ≥ 40 ml/min según la fórmula de Cockroft y Gault
- Capacidad para comprender y voluntad para firmar y otorgar el consentimiento informado por escrito.
- Capacidad del paciente, en opinión del investigador, para cumplir con todos los procedimientos y exploraciones del estudio

E.4

Principal exclusion criteria

- History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that, in the opinion of the investigator, renders the subject at high risk from treatment complications or might affect the interpretation of the results of the study.
- Presence of central nervous system or brain metastases.
- Life expectancy < 12 weeks.
- Pregnancy (positive pregnancy test) or lactation.
- Pre-existing sensory neuropathy > grade 1.
- Clinically significant cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication) or myocardial infarction within the last 12 months.
- Major surgery within 4 weeks of the start of study treatment, without complete recovery.
- Prior malignancy except for adequately treated basal cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other form of cancer from which the patient has been disease-free for 5 years

- Historia de otra enfermedad, disfunción metabólica, hallazgo en la exploración física o hallazgo de laboratorio clínico que haga sospechar de una enfermedad o
condición que, en opinión del investigador, pueda comprometer la seguridad del paciente por riesgo de complicaciones del tratamiento o pueda afectar a la
interpretación de los resultados del estudio.
- Presencia de metástasis en sistema nervioso central.
- Esperanza de vida < 12 semanas
- Mujeres embarazadas o en período de lactancia.
- Neuropatía previa > grado 1.
- Enfermedad cardíaca clínicamente significativa (por ejemplo insuficiencia cardíaca congestiva, enfermedad arterial coronaria y arritmias cardíacas no controladas con la medicación) o infarto de miocardio en los últimos 12 meses.
- Cirugía mayor en las 4 semanas previas al inicio del tratamiento del estudio, sin recuperación completa.
- Tumor maligno previo, excepto antecedentes de carcinoma de células basales de la piel o cáncer de cérvix estadio I o II adecuadamente tratado y actualmente en remisión completa o cualquier otra forma de cáncer de la que el paciente ha estado libre de enfermedad durante 5 años.

E.5 End points

E.5.1

Primary end point(s)

Phase I:
To determine the safety DLT for the AG-mFOLFOX combination defined by:
- Grade 3 - 4 non-haematological toxicity (except hypersensitive reactions; in case of grade 3 diarrhoea or emesis dose limitations will only be considered if these occur in spite of receiving optimal out-patient medical treatment)
- Grade 4 haematological toxicity (grade 4 thrombocytopenia (<25 x 109/L) or grade 4 neutropenia lasting ≥ 7 days, , or grade 3 thrombocytopenia with hemorrhage or ≥ Grade 3 febrile neutropenia: absolute neutrophil count < 1000 x 109/L and fever of > 38ºC)
- Any toxicity requiring a 2-week delay between cycles is also considered dose limiting.

Phase II:
- Overall survival al 12 months after treatment initiation.

Ensayo Fase I:
- Determinar la toxicidad limitante de dosis (TLD) para el régimen AG-mFOLFOX definido como:
- Toxicidades no hematológica grado 3 y 4 (excepto reacciones de hipersensibilidad; en caso de nausea y vómitos grado 3, solo será consideradas toxicidad limitante
de dosis si ocurren a pesar de haber recibido las adecuadas medidas de soporte y de apoyo).
- Toxicidades hematológicas grado 4: trombocitopenia grado 4 (<25 x 109/L) o
trombocitopenia grado 3 con hemorragia; neutropenia grado 4 con duración ≥ 7
días; o neutropenia febril ≥ grade 3 (RAN < 1000 x 109/L y fiebre > 38°C).
- Cualquier toxicidad que requiera un retraso de dos semanas será considerada una toxicidad limitante de dosis.

Ensayo Fase II:
- Supervivencia global a los 12 meses.

E.5.1.1

Timepoint(s) of evaluation of this end point

Phase I:
- To determine the safety DLT: during study treatment.

Phase II:
- Overall survival al 12 months.

Ensayo Fase I:
- Determinar la toxicidad limitante de dosis (TLD): durante el tratamiento en estudio.

Ensayo Fase II:
- Supervivencia global a los 12 meses.

E.5.2

Secondary end point(s)

Phase I:
- Overall response rate.
Phase II:
- Overall survival at 6 and 24 months.
- Time to tumor progression.
- Progression free survival.
- Overall survival.
- Objective radiographic response (ORR).
- CA 19-9 biomarker response.
- Safety profile using NCI-CTCAE v.4 criteria
- Quality of Life of the patients through the EORTC QLQ-C30 and EORTC QLQ-CIPN20 questionnaires

Ensayo fase I:
- Tasa de respuesta
Ensayo fase II:
- Tasa de supervivencia global a los 6 y 24 meses
- Tiempo a la progresión.
- Supervivencia libre de progresión .
- Supervivencia global.
- Respuesta radiográfica objetiva.
- Respuesta del marcador CA 19-9.
- Perfil de seguridad según criterios NCI-CTCAE versión 4
- Calidad de vida de los pacientes a través de los cuestionarios EORTC QLQ-C30
y EORTC QLQ-CIPN20.

E.5.2.1

Timepoint(s) of evaluation of this end point

PFS: date of disease progression or death for any reason (what happens first)TTP: date of disease progression
OS: date of death for any reason
ORR, CA 19-9, Safety and QoL: during treatment and follow-up period (if applicable)

SLP: la fecha en que se documenta la progresión de la enfermedad o la muerte por cualquier causa (lo que ocurra antes)
TTP: la fecha en que se documenta la progresión de la enfermedad
OS: la fecha en que se documenta la muerte por cualquier causa
ORR y CA 19-9, Safety y QoL: durante el tratamiento y seguimiento (si aplica)

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

E.6.7

Pharmacodynamic

Yes

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)

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

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

Yes

E.8.1.7.1

Other trial design description

Fase I: abierto con escalado de dosis. Fase II: aleatorizado y abierto.

Phase I of the study is an open label dose escalation trial. Phase II is a randomised, open label

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

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

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

When patient ends the follow-up period attending to the last follow-up visit. It is anticipated a follow-up period of one year after the date of last patient inclusion

El estudio se dará por finalizado cuando cada paciente reclutado haya concluido el período de seguimiento acudiendo a la última visita de seguimiento.
Está previsto un período de seguimiento de un año tras la inclusión del último paciente

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:

150

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

180

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)

when patient finished the study, the follow up will be done acoording to clinical practice for site participant in clinical trial.

Una vez que el pacientes finalice el estudio, el seguimiento se realizará siguiendo la práctica clínica habitual de cada uno de los centros participantes.

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

2015-06-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-06-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-04-10

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