Clinical Trials Register

Summary
EudraCT Number:	2009-011041-12
Sponsor's Protocol Code Number:	ET-A-018-09
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2009-06-04
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

France - ANSM

A.2

EudraCT number

2009-011041-12

A.3

Full title of the trial

Étude multicentrique de phase Ib-II en escalade de dose de la trabectédine (Yondelis®) en association avec l’oxaliplatine chez des patientes atteintes d’un cancer de l’ovaire avancé prétraité.

A.4.1

Sponsor's protocol code number

ET-A-018-09

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Pharma Mar S.A.
B.1.3.4	Country	Spain
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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 0.25 mg and 1.0 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharma Mar S.A.
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/03/171
D.3 Description of the IMP
D.3.1	Product name	Yondelis
D.3.2	Product code	ET-743
D.3.4	Pharmaceutical form	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	ET-743
D.3.9.3	Other descriptive name	Ecteinascidin
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	0.05 mg/ml
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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.2.5	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	Oxaliplatin
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	63121-00-6
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	5 mg/ml
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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

Pretreated Advanced Ovarian Cancer

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	PT
E.1.2	Classification code	10057529
E.1.2	Term	Ovarian cancer metastatic

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

Phase Ib stage: To determine the recommended dose (RD) of the combination of trabectedin and oxaliplatin in patients with advanced ovarian cancer.

Phase II

Phase II stage: To determine the antitumor activity of the combination of trabectedin and oxaliplatin, administered at the RD established in the phase Ib stage, in patients with advanced ovarian cancer.

E.2.2

Secondary objectives of the trial

Phase Ib only

To determine the efficacy of the combination of trabectedin and oxaliplatin.

Phase Ib/II

To determine the safety profile of this trabectedin-oxaliplatin regimen in this population.

To determine the pharmacokinetic (PK) profile for each drug when administered in combination.

To determine the pharmacogenomic (PGx) profile of tumor samples from the patients participating in this trial. Hypothesis-generating exploratory PGx analyses will be conducted to correlate the molecular parameters found in the tumor samples of the patients with the clinical results achieved with the trabectedin-oxaliplatin regimen.

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

PHARMACOGENOMIC STUDIES USING TUMOR TISSUE OF PATIENTS INCLUDED IN THE CLINICAL STUDY ET-A-0018-09

1. Determine the gene and protein expression profiles of tumor tissue of the patients included in the clinical study ET-A-018-09.
2. Determine the genotype of the SNP Asp1104His of XPG and other SNPs related to the mechanism of action (MOA) of trabectedin.
3. Correlate the gene and protein expression profiles and the SNP genotype with the clinical outcome of the patients treated with the combination trabectedin + oxaliplatin and the evolution of the disease.

E.3

Principal inclusion criteria

1. Age ≥ 18 years.
2. Eastern Cooperative Oncology group (ECOG) performance status (PS) ≤ 2.
3. Patients with histologically proven relapsed ovarian carcinoma.
4. Prior treatment with at least one line of platinum compounds and taxanes, with no more than two prior lines of platinum-based therapy, and no more than three prior lines of chemotherapy.
5. Recovered from toxicity associated with prior treatments to National Cancer Institute Common Terminology Criteria version 3.0 (NCI-CTCAE) grade 0/1 (except for alopecia).
6. Measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.0 (for phase II only).
7. Acceptable hematological and biochemical function, including: absolute neutrophil count (ANC) ≥ 1.5 x 109/l, platelet count > 100 x 109/l, creatinine < the upper limit of normal (ULN), total bilirubin ≤ ULN, transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] ≤ 2.5 x ULN. Total alkaline phosphatase (AP) ≤ 2.5 x ULN; if the value is > 2.5 x ULN, evaluate the hepatic AP isoenzyme and/or gamma-glutamyltransferase (GGT) and/or 5’ nucleotidase, whose values must be within the ULN.
8. Women of child-bearing potential must have a negative pregnancy test prior to the treatment initiation and use a medically approved method of contraception during the trial and for four months after the last administration of study drug.
9. Voluntarily signed and dated written informed consent prior to any specific study procedures.

E.4

Principal exclusion criteria

1. Pregnant or lactating women.
2. Prior exposure to trabectedin or oxaliplatin.
3. Known allergy to any component of trabectedin, oxaliplatin or dexamethasone.
4. Contraindications for the use of corticosteroids.
5. Clinical symptoms of brain metastasis.
6. History of another neoplastic disease (except basal cell carcinoma or uterine cervix carcinoma in situ adequately treated), unless in remission for ≥ 5 years (for phase II only).
7. Symptomatic sensitive neuropathy grade > 1 as per NCI-CTCAE, version 3.0.
8. Less than three weeks between treatment with radiotherapy, hormone therapy, biological therapy, investigational product or chemotherapy (six weeks for nitrosoureas or mitomycin-C) and inclusion.
9. Other serious and/or relevant diseases that, in opinion of the Investigator, are incompatible with the protocol (including any of the following):
a. History of cardiac disease, such as myocardial infarction, in the year prior to enrollment in the clinical trial, symptomatic/uncontrolled angina pectoris, congestive heart failure or uncontrolled cardiac ischemia, or arrhythmia, abnormal left ventricular ejection fraction, or uncontrolled arterial hypertension.
b. Active infection.
c. Active or chronic liver or renal disease.
d. Major surgery in the two weeks prior to entering the clinical trial.
10. Patients unable to comply with the study protocol owing to psychological, social or geographical reasons.
11. Participation in another clinical trial or concomitant treatment with any investigational product within 21 days prior to inclusion.

E.5 End points

E.5.1

Primary end point(s)

Phase Ib stage: The determination of the RD will be evaluated in patients who are treated and followed for at least one cycle of the combination, or who experience a DLT during the first cycle. The MTD will be the level at which ≥ 2/3 or ≥ 2/6 evaluable patients have a DLT in Cycle 1. The RD will be the dose level immediately below the MTD. A minimum of ten evaluable patients will be treated at the RD.

Phase II stage: Overall response rate (ORR), defined as the percentage of patients with confirmed objective response (OR), either complete (CR) or partial (PR) response according to the RECIST criteria.

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

Yes

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 of combination (first administration to humans of combination)

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

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

Information not present in EudraCT

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

Six months after the last treatment visit of the last evaluable patient included in the study or 12 months after the last patient is included, whichever occurs first.

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	No
F.1.1.1	In Utero	Information not present in EudraCT
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	Information not present in EudraCT
F.1.1.3	Newborns (0-27 days)	Information not present in EudraCT
F.1.1.4	Infants and toddlers (28 days-23 months)	Information not present in EudraCT
F.1.1.5	Children (2-11years)	Information not present in EudraCT
F.1.1.6	Adolescents (12-17 years)	Information not present in EudraCT
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	No
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	64

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

2009-07-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-07-23

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

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