Clinical Trials Register

Summary
EudraCT Number:	2010-021382-78
Sponsor's Protocol Code Number:	RXT-MISO-10
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2010-08-09
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

Spain - AEMPS

A.2

EudraCT number

2010-021382-78

A.3

Full title of the trial

Ensayo fase I/II de escalada de dosis de radioterapia sobre regiones hipóxicas determinadas con F18-fluoromisonidazol (FMISO)-PET/TC en cáncer de pulmón.

A.3.1

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

Dose radiotherapy for lung cancer treatment.

Escalada de dosis de radioterapia para el tratamiento de cáncer de pulmón.

A.4.1

Sponsor's protocol code number

RXT-MISO-10

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	Consorci Mar Parc de Salut de Barcelona (Parc de Salut MAR)
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	Instituto de Salut Carlos III (FIS)
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	Hospital de l'Esperança
B.5.2	Functional name of contact point	Servicio de Oncología Radioterápica
B.5.3	Address:
B.5.3.1	Street Address	Sant Josep de la Muntanya, 12
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08024
B.5.3.4	Country	Spain
B.5.4	Telephone number	00349336741444144
B.5.5	Fax number	00349336742714271
B.5.6	E-mail	malgara@parcdesalutmar.cat

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.3.1	Product name	f18-Fluormisonidazol (FMISO)
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	No aplica
D.3.9.1	CAS number	150196-34-2
D.3.9.2	Current sponsor code	[18F]-FMISO
D.3.9.3	Other descriptive name	1H-1-(3-[18F]-fluoro-2-hydroxy-propyl)-2-nitroimidazol
D.3.10	Strength
D.3.10.1	Concentration unit	Bq/kg becquerel(s)/kilogram
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	6
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	Yes
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

Lung cancer.

Cáncer de pulmón.

E.1.1.1

Medical condition in easily understood language

Lung cancer.

Cáncer de pulmón.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

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 maximal tolerated dose (MTD) of radiotherapy in lung cancer patients, who are candidates to radical treatment with chemotherapy or radiotherapy. Doses will be increased according to hypoxic regions of the tumor measured by FMISO-PET. Phase II: To determine the clinical efficacy of the MTD in a group of 30 lung cancer patients evaluating tumoral response rate.

FASE I: Determinar la dosis máxima tolerada (DMT) de radioterapia, que se puede administrar en pacientes con cáncer de pulmón candidatos a tratamiento radical con quimio y radioterapia, escalando la dosis sobre las regiones hipóxicas del tumor definidas mediante FMISO-PET. FASE II: Determinar la eficacia de la dosis máxima tolerada en un grupo de 30 pacientes, evaluando la tasa de respuestas.

E.2.2

Secondary objectives of the trial

To determine local disease free survival, distance disease free survival, and acute and chronic toxicity.

Determinar la supervivencia libre de enfermedad local, la supervivencia libre de enfermedad a distancia y la toxicidad aguda y crónica.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

a) Men or women who are between 18 and 65 years of age
b)Subjects with histologically or cytologically confirmed non-small cell carcinoma
c)Stage III
d)Karnofsky index ≥ 70 %.
e)Forced Expiratory Volume in 1 second (FEV1) equal or greater than 1 Liter.
f)Measurable disease on CT scan of radiotherapy planning.
g)Lung percentage (both lungs excluding PTV or planned volume) that will recive a dose > 20 Gy (V20 ) must be less or equal of 30 %.
h)The esophagus volume vill be delimited withoth excluding PTV. The percentage of esophagus that will recive a dose > 60 Gy (V60) mus be less or equal to 30% and the mean dose in esophagus (MED) less or equal to 34 Gy.
i) Concomitanr chemotherapy.
j) Biochemistry and blood analysis. Neutrophils ≥ 1500/µl; platelets ≥ 100000/µl; creatinine ≤ 2 mg/dl, hepatic transaminases < 2,5 times the upper limit of normality, bilirubin < 1,5 times upper limit of normality; alkaline phosphatase < 2,5 times the upper limit of normality.
k) Women must commit to consistent and correct use of an acceptable method of birth control.
l) Subject with a weigth loss <10% in the previous three months of the disgnosis.

a)Edad igual o superior a 18 años y hasta los 65 años.
b)Diagnóstico cito o histológico de carcinoma no célula pequeña de pulmón.
c)Estadio III.
d)Indice de Karnofsky ≥ 70 %.
e)FEV1 igual o superior a 1 Litro.
f)Enfermedad medible en la TC de planificación de radioterapia.
g)El porcentaje de pulmón (ambos pulmones excluyendo el PTV ó volumen planificado) que recibe una dosis > 20 Gy (V20 ) debe ser menor o igual de 30 %.
h)Se delimitará todo el volumen esofágico sin excluir PTV. El porcentaje de esófago que recibe una dosis > 60 Gy (V60) debe ser menor ó igual del 30% y la dosis media en esófago (MED) menor o igual de 34 Gy.
i)Quimioterapia concomitante.
j)Analítica: neutrófilos ≥1500/µl; plaquetas ≥100000/µl; creatinina ≤ 2 mg/dl, transaminasas < 2,5 veces el límite de la normalidad, bilirrubina < 1,5 veces el límite de la normalidad, fosfatasas alcalinas < 2,5 veces el límite de la normalidad.
k)Las pacientes en edad fértil deberán usar un método anticonceptivo adecuado.
l)Pacientes con pérdida de peso <10% en los tres meses anteriores al diagnóstico.

E.4

Principal exclusion criteria

a)Small-cell carcinoma
b)Pleural or pericardic effusion with positive cytology
c)Supraclavicular adenopathy positive
d)Superior vena cava syndrome
e)Previous thoracic radiation.
f)Sensitive neuropathy > grade I following NCI CTCv 3.0 criteria
g)Severe comorbididy (acute myocardial infacrtion within 3 nmonth of inclusion, cardiac arrithmia or non-controlled hypertension )
h)Treatments that can interfere with the pharmacokinetic or pharmacodynamic of (18F)-FMISO.
i)Pregnant or breast-feeding females
j)Subjects older than 65 years.
k)Subjects with renal and/or hepatic function impairment or failure. A renal impairment is considered if serum creatinine ≥ 2 mg/dl and an hepatic impairment is diagnosed if bilirubin ≥ 1,5 times upper limit normal and or tranbaamionas (ASAT-ALAT) ≥ 2,5 times the upper limit of normality.

a)Carcinoma de célula pequeña.
b)Derrame pleural ó pericárdico con citología positiva.
c)Adenopatía supraclavicular positiva.
d)Síndrome de vena cava superior.
e)Irradiación torácica previa.
f)Neuropatía sensitiva > grado I según criterios del NCI CTCv 3.0
g)Comorbilidad asociada severa (IAM en los tres meses previos, arritmia o HTA mal controlada).
h)Pacientes con tratamientos que interfieran en la farmacocinética o farmacodinamia del (18F)-FMISO.
i)Pacientes lactantes.
j)Pacientes mayores de 65 años.
k)Pacientes con disfunción renal y/o hepática, considerándose una disfunción renal la presencia de una creatinina en sangre ≥ 2 mg/dl y una disfunción hepática a la presencia de una cifra de bilirrubina ≥ 1,5 veces el límite de la normalidad y/o la presencia de una cifra de transaminasas (ASAT-ALAT) ≥ 2,5 veces el límite de la normalidad.

E.5 End points

E.5.1

Primary end point(s)

-Maximal tolerated dose (MTD) evaluation: acute toxicity will be collected (? 90 days after radiotherapy) following the grades of the NCI CTC (Commom Toxicity Criteria) version 3.0. Late effects (collected > 90 days after radiotherapy) will be collected following the RTOG Late Radiation Morbidity Scoring Scale. The adverse vents directly attributed to radiotherapy will be collected following the NCI CTCv3.0.
- Efficacy evaluation: complete or partial remissions

-Valoración de dosis máxima de tolerancia: se recogerá la toxicidad aguda (? 90 días desde el inicio de la radioterapia) según las escalas del NCI CTC (Commom Toxicity Criteria) versión 3.0. Los efectos tardíos (> 90 días desde el inicio de la radioterapia) serán recogidos de acuerdo con la escala de la RTOG Late Radiation Morbidity Scoring Scale. Los efectos secundarios atribuibles directamente a la quimioterapia se recogerán mediante la escala del NCI CTCv3.0.
- Valoración de eficacia: porcentaje de remisiones completas y parciales.

E.5.1.1

Timepoint(s) of evaluation of this end point

In both, Phase I and Phase II, subjects will be evaluated at least once per week during therapy, collecting acute toxicity. After that, evaluations will be done monthly and then every three months to complete one year.
In the Phase II part, the response variable will be obtained by a CT (one month aftter therapy).

Tanto en el ensayo fase I como en el fase II, los pacientes serán evaluados al menos 1 vez/semana durante el tratamiento con quimio-radioterapia, recogiendo la toxicidad aguda. Seguidamente, se realizaran evaluaciones periódicas al mes y posteriormente cada 3 meses hasta completar un año.

E.5.2

Secondary end point(s)

Efficacy evaluated in terms of global survival, local disease free survival, distance disease free survival. In addition acute and chronic toxicity.

Eficacia valorada en términos de supervivencias global, específica, libre de enfermedad local y libre de enfermedad a distancia. Asimismo se valorará toxicidad aguda y crónica.

E.5.2.1

Timepoint(s) of evaluation of this end point

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

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

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

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

Subjects may withdraw from the study by investigator in case of the appearance of side effects and in case of suspect of non-compliance with the protocol.

El ensayo clínico puede ser interrumpido a discreción del investigador principal en caso aparición de acontecimientos adversos o incumplimiento por parte de los sujetos.

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:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After the trial subject will receive standard medical care.

Una vez finalizado el ensayo clínico, el paciente recibirá tratamiento médico adecuado.

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

2011-11-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-11-08

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

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