Clinical Trials Register

Summary
EudraCT Number:	2009-016138-29
Sponsor's Protocol Code Number:	APL-C-001-09
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-06-18
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

Portugal - INFARMED

A.2

EudraCT number

2009-016138-29

A.3

Full title of the trial

Randomized, Multicenter, Open-label, Phase III Study of Plitidepsin in Combination with Dexamethasone vs. Dexamethasone Alone in Patients with Relapsed/Refractory Multiple Myeloma.

Estudo Aberto, Aleatorizado, Multicêntrico, de Fase III, de Plitidepsina em Associação com Dexametasona versus Dexametasona Isolada em Doentes com Mieloma Múltiplo Recidivante/Refratário

A.3.1

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

Study of Plitidepsin in Combination with Dexamethasone vs. Dexamethasone Alone in Patients with Relapsed/Refractory Multiple Myeloma.

Estudo de Plitidepsina em Associação com Dexametasona versus Dexametasona Isolada em Doentes com Mieloma Múltiplo Recidivante/Refratário

A.3.2

Name or abbreviated title of the trial where available

ADMYRE

A.4.1

Sponsor's protocol code number

APL-C-001-09

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	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	Pharma Mar, S.A.
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	Pharma Mar, S.A.
B.5.2	Functional name of contact point	Clinical Trials
B.5.3	Address:
B.5.3.1	Street Address	Av. de los Reyes, 1 - Pol. Ind. "La Mina"
B.5.3.2	Town/ city	Colmenar Viejo (Madrid)
B.5.3.3	Post code	28770
B.5.3.4	Country	Spain
B.5.4	Telephone number	+3491846 60 00
B.5.5	Fax number	+3491846 60 03
B.5.6	E-mail	clinicaltrials@pharmamar.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/04/245
D.3 Description of the IMP
D.3.1	Product name	APLIDIN (plitidepsin)
D.3.2	Product code	Not applicable
D.3.4	Pharmaceutical form	Powder and solvent 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	plitidepsin
D.3.9.1	CAS number	137219-37-5
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	2
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	Comparator
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	FORTECORTIN 4 mg Tabletten
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	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	Dexamethasone
D.3.9.1	CAS number	50-02-2
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	4
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

Relapsed/Refractory Multiple Myeloma

E.1.1.1

Medical condition in easily understood language

Multiple Myeloma

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	10028228
E.1.2	Term	Multiple myeloma
E.1.2	System Organ Class	100000004864

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 compare the efficacy of plitidepsin in combination with dexamethasone vs. dexamethasone alone as measured by progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (MM).

E.2.2

Secondary objectives of the trial

To evaluate tumor response according to the International Myeloma Working Group (IMWG) criteria.
To assess duration of response (DR) and overall survival (OS).
To assess efficacy in patients who undergo crossover from dexamethasone alone to plitidepsin and dexamethasone combination.
To characterize and compare the safety profile on both arms in this population.
To characterize the pharmacokinetics (PK) and pharmacokinetic /pharmacodynamic (PK/PD) relationship.

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

QT substudy is to assess the potential effects of plitidepsin administered at a therapeutic dose on the duration of the QT/QTc interval, measured by ECGs, in patients with relapsed/refractory multiple myeloma.

E.3

Principal inclusion criteria

1. Concomitant diseases/conditions:
a) History or presence of angina, myocardial infarction, clinically relevant valvular heart disease, cardiac amyloidosis or congestive heart
failure within the last 12 months.
b) Symptomatic arrhythmia (excluding anemia-related sinusal tachycardia grade <= 2) or any arrhythmia requiring ongoing treatment,
and/or prolonged QT-QTc grade >= 2; or presence of unstable atrial fibrilation. Patients with stable atrial fibrillation on treatment are allowed provided they do not meet any other cardiac or prohibited drug exclusion criterion.
c) Active uncontrolled infection.
d) Morphological or cytological features of myelodysplasia and/or postchemotherapy aplasia on BM assessment.
e) Myopathy > grade 2 or any clinical situation that causes significant and persistent elevation of CPK (>2.5 x ULN in two different determinations performed one week apart).
f) Known human immunodeficiency virus (HIV) infection (HIV testing is not required unless infection is clinically suspected).
g) Known active hepatitis B or C virus (HBV or HCV) infection.
h) Limitation of the patient?s ability to comply with the treatment or follow-up requirements.
i) Any other major illness that, in the Investigator´s judgment, will substantially increase the risk associated with the patient´s
participation in this study.
j) Peripheral neuropathy > grade 2.
2. Women who are pregnant or breast feeding.
3. Concomitant medications that include corticosteroids, chemotherapy, or other therapy that is or may be active against MM, within two weeks prior to Cycle 1 Day 1. Concurrent corticosteroids are allowed, provided
they are administered at an equivalent prednisone dose of <= 10 mg daily, as premedication for blood products only.
4. Known history of peptic ulcer and/or major upper gastrointestinal bleeding episode occurring during last year before study entry and/or
related to prior steroid-based therapy.
5. Relevant history of mood-disturbances changes associated with previous steroid-based therapy.
6. Disease-related symptomatic hypercalcemia despite optimal medical therapy.
7. Known hypersensitivity to any involved study drug or any of its formulation components.

E.4

Principal exclusion criteria

1. Concomitant diseases/conditions:
a) History or presence of angina, myocardial infarction, clinically relevant valvular heart disease, cardiac amyloidosis or congestive heart failure within the last 12 months.
b) Symptomatic arrhythmia (excluding anemia-related sinusal tachycardia grade <= 2) or any arrhythmia requiring ongoing treatment, and/or prolonged QT-QTc grade >= 2; or presence of unstable atrial fibrilation. Patients with stable atrial fibrillation on treatment are allowed provided they do not meet any other cardiac or prohibited drug exclusion criterion.
c) Active uncontrolled infection.
d) Morphological or cytological features of myelodysplasia and/or post-chemotherapy aplasia on BM assessment.
e) Myopathy > grade 2 or any clinical situation that causes significant and persistent elevation of CPK (>2.5 x ULN in two different determinations performed one week apart).
f) Known human immunodeficiency virus (HIV) infection (HIV testing is not required unless infection is clinically suspected).
g) Known active hepatitis B or C virus (HBV or HCV) infection.
h) Limitation of the patient?s ability to comply with the treatment or follow-up requirements.
i) Any other major illness that, in the Investigator?s judgment, will substantially increase the risk associated with the patient?s participation in this study.
j) Peripheral neuropathy > grade 2.
2. Women who are pregnant or breast feeding.
3. Concomitant medications that include corticosteroids, chemotherapy, or other therapy that is or may be active against MM, within two weeks prior to Cycle 1 Day 1. Concurrent corticosteroids are allowed, provided they are administered at an equivalent prednisone dose of <= 10 mg daily, as premedication for blood products only.
4. Known history of peptic ulcer and/or major upper gastrointestinal bleeding episode occurring during last year before study entry and/or related to prior steroid-based therapy.
5. Relevant history of mood-disturbances changes associated with previous steroid-based therapy.
6. Disease-related symptomatic hypercalcemia despite optimal medical therapy.
7. Known hypersensitivity to any involved study drug or any of its formulation components.

E.5 End points

E.5.1

Primary end point(s)

PFS, according to IRC assessment, as per intention-to-treat (ITT) analysis.

E.5.1.1

Timepoint(s) of evaluation of this end point

Estimated average: 5 months. From randomization to the first evidence of progressive disease or death due to any cause

E.5.2

Secondary end point(s)

Response rate
Duration of Response
Overall Survival

E.5.2.1

Timepoint(s) of evaluation of this end point

Response rate: Every 4 weeks untill progression
Duration of Response: Estimated average: 3 months. From the date of first documentation of response to the date of disease
progression or death.
Overall Survival: Estimated average: 9 months. From randomization to the first evidence of progressive disease or death due to any cause

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

Yes

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)

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

Dexamethasone

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Austria

Belgium

Czech Republic

France

Germany

Greece

Ireland

Italy

Korea, Republic of

Netherlands

New Zealand

Poland

Portugal

Spain

Taiwan

United Kingdom

United States

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

Planned study termination date: it will be set after the occurrence of 80% of death events, 24 months after the accrual of the last randomized patient, or IDMC recommendation (whichever occurs first). This is the estimated time to obtain the data on PFS as primary objective of the clinical trial, and OS.
The duration of this study is prolonged for six additional months, in order to continue follow-up in the alive patients.

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 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:

138

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

112

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

125

F.4.2.2

In the whole clinical trial

250

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)

Not applicable

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

2013-08-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-10-04

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-11-20

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