Clinical Trials Register

Summary
EudraCT Number:	2015-004472-30
Sponsor's Protocol Code Number:	MITO-23
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2017-12-21
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2015-004472-30

A.3

Full title of the trial

Randomized phase III trial on Trabectedin (ET-743) vs clinician's choice
chemotherapy in recurrent ovarian, primary peritoneal or fallopian tube
cancers of BRCA mutated or BRCAness phenotype patients
MITO-23

Estudio en fase III aleatorizado sobre trabectedina (ET 743) frente a la
quimioterapia elegida por el clínico en pacientes con cáncer ovárico,
peritoneal primario o tubárico con fenotipo de mutación en BRCA o
BRCAness – MITO-23

A.3.1

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

fallopian tube cancers of BRCA mutated or BRCAness phenotype treated
with Trabectedin compared to a standard treatment.

calcular la supervivencia global de pacientes con recidiva de tumor ovárico,
de las Trompas de Falopio o primitivo de peritoneo con mutaciones del
BRCA o con fenotipo BRCAness, tratados con Trabectedina, respecto a un
tratamiento estándar.

A.4.1

Sponsor's protocol code number

MITO-23

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02903004

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	Fondazione IRCCS Istituto Nazionale dei Tumori
B.1.3.4	Country	Italy
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	Pharma Mar
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione IRCCS Istituto Nazionale dei Tumori
B.5.2	Functional name of contact point	Clinical Trial Center
B.5.3	Address:
B.5.3.1	Street Address	Via Giacomo Venezian 1
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20133
B.5.3.4	Country	Italy
B.5.4	Telephone number	3902239038183063
B.5.5	Fax number	390223903991
B.5.6	E-mail	trialcenter@istitutotumori.mi.it
B.Sponsor: 2
B.1.1	Name of Sponsor	Grupo Español de Investigacion en Cancer de Ovario GEICO
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	Pharma Mar
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	Ibertrials
B.5.2	Functional name of contact point	Amelia Alcazar
B.5.3	Address:
B.5.3.1	Street Address	C/ Camino Fuente de la Mora, 9, 1º
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28050
B.5.3.4	Country	Spain
B.5.4	Telephone number	3491629813121
B.5.5	Fax number	34914474211
B.5.6	E-mail	amelia.alcazar@ibertrials.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	Yondelis 1 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharma Mar SA
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	Yondelis 1 mg
D.3.2	Product code	ET-743
D.3.4	Pharmaceutical form	Powder and solvent for 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	TRABECTEDIN
D.3.9.1	CAS number	114899-77-3
D.3.9.2	Current sponsor code	CT 7917
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB20756
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	1.3
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	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

Patient with recurrence of ovarian tumor, fallopian tube or peritoneum
primitive that has a BRCA mutation or BRCAness phenotype.

Paciente con recidiva de tumor ovárico, de trompa de Falopio o primitivo
de peritoneo que presenta una mutación del BRCA o del fenotipo
BRCAness.

E.1.1.1

Medical condition in easily understood language

Patients with ovarian, primary or tubal peritoneal cancer with mutation
phenotype in BRCA or BRCAness

Pacientes con cáncer ovárico, peritoneal primario o tubárico con fenotipo
de mutación en BRCA o BRCAness

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	LLT
E.1.2	Classification code	10033271
E.1.2	Term	Ovarian neoplasia
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10016183
E.1.2	Term	Fallopian tube cancer NOS
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10026340
E.1.2	Term	Malignant neoplasm of peritoneum, unspecified
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

The main objective is to compare overall survival (OS) between
treatment groups

El objetivo principal es comparar la supervivencia global (SG) entre los
grupos de tratamiento

E.2.2

Secondary objectives of the trial

Secondary:
The secondary objectives are to compare the treatment groups in terms
of:
• Progression free survival (PFS). In case of CA-125 progression
according to GCIG criteria is documented, a confirmatory CT scan and a
radiological CT progression will be required.
• Radiological response rate (in patients with measurable disease)
• Duration of response
• CA-125 response rate per GCIG and change in CA-125
• Toxicity profile
• Quality of Life assessments using QLQ-C30 and QLQ-OV28

Secundarios:
Los objetivos secundarios son comparar los siguientes parámetros entre
los grupos de tratamiento:
• La supervivencia sin progresión (SSP). Si se documenta progresión
del CA-125 de acuerdo con los criterios del GCIG, se requerirá la confirmación la progresión mediante TC y el estudio radiológico de la progresión.
• Tasa de respuesta radiológica (en pacientes con enfermedad
mensurable)
• Duración de la respuesta
• Tasa de respuesta de CA-125 según el GCIG y cambio del CA-125
• Perfil de toxicidad
• Evaluaciones de la calidad de vida mediante QLQ-C30 y QLQ-OV28

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

Translational Study.- The translational end points are aimed at
evaluating the impact of altered gene and microRNA (miRNA) expression
on trabectedin efficacy. This analysis will allow considering which genes
are involved in the so called BRCAness phenotype (Rigakos G, Razis E.
BRCAness: finding the Achilles heel in ovarian cancer.Oncologist.
2012;17:956-62) thought to be more sensitive to this treatment, and
how these genes are regulated.
Storage will be centralized at Fondazione IRCCS Istituto Nazionale
Tumori

Estudio traslacional.- Los criterios traslacionales de valoración están
dirigidos a la evaluación del impacto de la alteración de la expresión de
los genes y del microRNA (miRNA) sobre la eficacia de la trabectedina.
Este análisis permitirá considerar cuáles son los genes implicados en el
denominado fenotipo BRCAness (Rigakos G, Razis E. BRCAness: finding
the Achilles heel in ovarian cancer. Oncologist. 2012;17:956-62), el cual
se cree que es más sensible a este tratamiento, y el modo en que se
regulan estos genes.
La conservación se centralizará en Fondazione IRCCS Istituto Nazionale
Tumori

E.3

Principal inclusion criteria

Inclusion criteria
1. Female of age 18 years or older
2. Histologically or cytologically documented invasive epithelial ovarian
cancer, primary peritoneal carcinoma, or fallopian tube cancer
3. Platinum resistant or sensitive patients with either:
a. BRCA mutated patients
b. BRCAness phenotype patients: patients who have received and
responded (subsequent PFI>6 months) to at least 2 previous platinum
based chemotherapy lines
c. Platinum sensitive patients who are not able to receive or not willing
to receive other platinum treatments
4. Measurable and evaluable disease per RECIST 1.1(Subjects with
isolated rising CA-125 without radiologically visible disease are
excluded)
5. ECOG performance status 0 or 1
6. No limits in the number of previous chemotherapy lines, previous
treatment with parp inhibitors is allowed
7. Left Ventricular Ejection Fraction (LVEF) ≥ institutional lower limit
normal
8. Life expectancy of at least 3 months
9. Adequate organ functions:
a. Hematopoietic: Absolute neutrophil count ≥ 1,500/mm3;
Platelet count ≥ 100,000/mm3; Hemoglobin ≥ 9 g/dl
b. Hepatic: AST and ALT ≤ 1.5 times upper limit of normal
(ULN)* ; Alkaline Phosphatase ≤ 2.5 times ULN* ; Bilirubin ≤ 1.5 times
ULN. NOTE: * ≤ 3 times ULN if liver metastases are present
c. Renal: Creatinine Clearance ≥ 45 ml/min or Serum Creatinine ≤1.5 x
ULN
d. Serum Albumin >2.5 g/dl
10. No other invasive malignancy within the past 3 years except nonmelanoma
skin cancer or in situ cervical cancer (patients with previous
cancers may be enrolled providing that no recurrences have be reported
in the last 3 years)
11. Written Informed Consent
12. Adequately recovered from the acute toxicity of any prior treatment
13. For agents in the standard arm, also refer to the local prescribing
information

1. Mujeres de edad igual o superior a 18 años
2. Cáncer epitelial ovárico, carcinoma peritoneal primario o cáncer
tubárico, invasivos y demostrados histológica o citológicamente cáncer
3. Pacientes resistentes o sensibles a platino con cualquiera de los
siguientes:
a. Mutación de BRCA
b. Fenotipo BRCAness: pacientes que han recibido y respondido
(ulterior PFI > 6 meses) como mínimo a 2 líneas previas de
quimioterapia con platino
c. Pacientes sensibles a platino que no pueden o no quieren recibir
otros tratamientos con platino
4. Enfermedad mensurable y evaluable según los RECIST 1.1 (se
excluye a pacientes con elevación aislada de CA-125 sin enfermedad
radiológicamente visible)
5. Estado funcional ECOG 0 o 1
6. Número ilimitado de líneas previas de quimioterapia; se permite el
tratamiento previo con inhibidores de la parp
7. Fracción de eyección ventricular izquierda (FEVI) ≥ límite inferior
normal del centro
8. Esperanza de vida al menos de 3 meses.
9. Funciones orgánicas adecuadas:
a. Hematopoyética: Recuento absoluto de neutrófilos
≥ 1500/mm3.; Recuento plaquetario ≥ 100000/mm3; hemoglobina ≥ 9
g/dl
b. Hepática: AST y ALT ≤ 1,5 x límite superior normal (LSN)*; fosfatasa
alcalina ≤ 2,5 x LSN*; bilirrubina ≤ 1,5 x LSN. NOTA: * ≤ 3 x el LSN si
hay metástasis hepáticas
c. Renal: Aclaramiento de creatinina ≥ 45 ml/min o creatinina sérica ≤
1,5 x LSN
d. Albúmina sérica > 2,5 g/dl
10. Ninguna otra neoplasia maligna invasiva durante los 3 años
precedentes, excepto cáncer cutáneo no melanomatoso o cáncer cervical
in situ (puede incluirse a pacientes con cánceres previos siempre que no
se haya diagnosticado una recidiva en los 3 años precedentes)
11. Consentimiento informado por escrito
12. Recuperación adecuada de la toxicidad aguda de cualquier
tratamiento previo
13. En cuanto a los agentes del grupo estándar, consúltense también
las advertencias, precauciones y contraindicaciones de las fichas
técnicas locales

E.4

Principal exclusion criteria

Exclusion criteria
1. Prior exposure to trabectedin
2. Known hypersensitivity to any of the components of the trabectedin
i.v. formulation or dexamethasone
3. Subjects with borderline ovarian cancer, ie. Subject with low
malignant potential tumors are excluded
4. At least 2 reported responses to platinum (i.e. subsequent recurrences
at least 6 months after the first and the second platinum based
treatment), unless BRCA mutation is documented.
5. Less than 4 weeks from last dose of therapy with any investigational
agent, or chemotherapy
6. History of another neoplastic disease (except basal cell carcinoma or
cervical carcinoma in situ adequately treated) unless in remission for 3
years or longer
7. Known clinically relevant CNS metastases, unless treated and
asymptomatic
8. Other serious illnesses, such as:
a. Congestive heart failure or angina pectoris; myocardial infarction
within 1 year before enrolment; uncontrolled arterial hypertension or
arrhythmias.
b. Psychiatric disorder that prevents compliance with protocol.
c. Active viral hepatitis; or chronic liver disease.
d. Active infection.
e. Any other unstable medical conditions.

Criterios de exclusión
1. Exposición previa a trabectedina
2. Hipersensibilidad conocida a cualquiera de los componentes de la
formulación IV de trabectedina o a dexametasona
3. Pacientes con cáncer ovárico de baja malignidad (borderline), es
decir, se excluirá a las pacientes con tumores de bajo potencial maligno
4. Menos de 2 respuestas documentadas a platino (es decir, recidivas
subsiguientes al menos 6 meses después del primer y del segundo
tratamiento con platino), a menos que se documente una mutación de
BRCA.
5. Menos de 4 semanas desde la última dosis de tratamiento con
cualquier agente experimental o quimioterapia
6. Antecedentes de otra neoplasia (excepto carcinoma de células
basales o carcinoma cervical in situ adecuadamente tratado) a menos
que se mantenga la remisión durante 3 años o más
7. Metástasis conocidas y clínicamente relevantes en el SNC, a menos
que se hayan tratado y no condicionen síntomas
8. Otras enfermedades graves como:
a. Insuficiencia cardíaca congestiva o angina pectoris; infarto de
miocardio en el año previo a la inclusión; hipertensión arterial no
controlada o arritmias.
b. Trastorno psiquiátrico que impida el cumplimiento del protocolo.
c. Hepatitis viral activa o hepatopatía crónica.
d. Infección activa.
e. Cualquier otra enfermedad médica inestable.

E.5 End points

E.5.1

Primary end point(s)

Efficacy
Efficacy will be evaluated based on OS and PFS.
• OS will be measured from the date of randomization to death due to
any cause
• PFS will be measured from the date of randomization to the date of
first observed disease progression (relapse) or the date of death due to any cause (if before progression).
Safety
Descriptive summary tables will be presented on all safety parameters
by treatment group. Patients will be monitored for adverse events using
the NCI-CTCAE version 4.0. Treatment-emergent adverse events and
safety laboratory parameters will be summarized by treatment group
and NCI-CTCAE v4.0 grade.
Quality of life will be evaluated QLQ-C30 and QLQ-OV28 questionnaire.

Eficacia
La eficacia se evaluará de acuerdo con la SG y la SSP.
• La SG se determinará desde la fecha de la aleatorización hasta la
muerte por cualquier causa
• La SSP se determinará desde la fecha de la aleatorización hasta la
fecha de la primera progresión observada de la enfermedad (recaída) o
la fecha de muerte por cualquier causa (si se produce antes de la
progresión).
Seguridad
Se presentarán resúmenes tabulados descriptivos de todos los
parámetros de seguridad por grupo de tratamiento. Se vigilará la
aparición de acontecimientos adversos mediante los NCI-CTCAE versión
4.0. Se resumirán los acontecimientos adversos inducidos por el
tratamiento y los parámetros analíticos de seguridad por grupo de
tratamiento y grado de los NCI- CTCAE, v4.0.
La calidad de vida se evaluará mediante los cuestionarios QLQ-C30 y
QLQ-OV28.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary objetive is to compare the treatment groups in terms of
overall survival (OS)

El objetivo principal es comparar los grupos de tratamiento en términos
de supervivencia general (OS)

E.5.2

Secondary end point(s)

Progression free survival (PFS) in case of CA125 progression according
to GCIG criteria is documented, a confirmatory CT scan and a radiological
CT progression will be required.

Se documenta la supervivencia libre de progresión (PFS) en el caso de la
progresión de CA125 según los criterios de GCIG, se requerirá una TC
confirmatoria y una progresión radiológica de la TC.

E.5.2.1

Timepoint(s) of evaluation of this end point

PFS will be measured from the date of randomization to the date of first
observed disease progression (relapse) or the date of death due to any
cause (if before progression)

La PFS se medirá desde la fecha de asignación al azar hasta la fecha de
la primera progresión de la enfermedad observada (recaída) o la fecha
de muerte por cualquier causa (si antes del progreso)

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

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

Yes

E.8.2.3.1

Comparator description

Pegylated Liposomal Doxorubicin 40 mg/mq q 28 or Topotecan 4 mg/mq dd 1,8,15 q 28 or Gemcitabina 100

Pegylated Liposomal Doxorubicin 40 mg/mq q 28 or Topotecan 4 mg/mq dd 1,8,15 q 28 or Gemcitabine 100

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

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

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

LVLS

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:

200

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

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