Clinical Trials Register

Summary
EudraCT Number:	2004-001117-34
Sponsor's Protocol Code Number:	APL-B-013-02
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-02-20
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2004-001117-34

A.3

Full title of the trial

A Phase II Multicenter,Open-Label, Clinical And Pharmacokinetic Study Of Aplidin As A 1-Hour Weekly IV Infusion, In Patients With Relapsed Or Refractory aggressive non-Hodgkin’s Lymphoma.

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

APL-B-013-02

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

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
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	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	Aplidin (Plitidepsin)
D.3.4	Pharmaceutical form	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.3.9.1	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)	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	Yes
D.3.11.13.1	Other medicinal product type	depsipetide ciclico

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

Aggressive non-Hodgkin’s Lymphoma.

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	HLGT
E.1.2	Classification code	10025321
E.1.2	Term	Lymphomas non-Hodgkin's T-cell

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 assess the anti-tumour activity of Aplidin given as a 1-hour weekly IV infusion, in patients with aggressive non-Hodgkin’s Lymphoma, relapsing or refractory to a prior therapy.

E.2.2

Secondary objectives of the trial

To further investigate the safety profile of Aplidin given as 1-hour weekly IV infusion in this patient population. To obtain additional pharmacokinetic information for Aplidin given as 1-hour weekly IV infusion in patients with aggressive non-Hodgkin’s Lymphoma.

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

ALTRI SOTTOSTUDI: Farmacogenomica

E.3

Principal inclusion criteria

1. Written informed consent obtained before starting any study-specific procedure. 2. Histologically confirmed aggressive lymphomas, including the following: 2.1 B-Cell neoplasms. 2.1.1 Precursor B-cell neoplasm 2.1.1.1.1 Precursor B-lymphoblastic lymphoma 2.1.2 Mature (peripheral) B-cell neoplasms 2.1.2.1. 1 Follicular lymphoma (histologic conversion) 2.1.2.1. 2 Mantle-cell lymphoma (diffuse pattern or blastic variant) 2.1.2.1. 3 Diffuse large B-cell lymphoma 2.1.2.1. 4 Mediastinal large B-cell lymphoma 2.1.2.1. 5 Burkitt’s lymphoma/Burkitt cell leukemia 2.2 T-cell and NK-cell neoplasms 2.2.1 Precursor T-cell neoplasm 2.2.1.1.1 Precursor T-lymphoblastic lymphoma 2.2.2 Mature (peripheral) T-cell neoplasms 2.2.2.1.1 Aggressive NK-cell leukemia 2.2.2.1.2 Adult T-cell lymphoma/leukemia (HTLV1) 2.2.2.1.3 Extranodal NK/T-cell lymphoma, nasal type 2.2.2.1.4 Enteropathy-type T-cell lymphoma 2.2.2.1.5 Hepatosplenic gamma-delta T-cell lymphoma 2.2.2.1.6 Subcutaneous panniculitis-like T-cell lymphoma 2.2.2.1.7 Anaplastic large-cell lymphoma, T/null cell, primary cutaneous type 2.2.2.1.8 Peripheral T-cell lymphoma, not otherwise characterized 2.2.2.1.9 Angioimmunoblastic T-cell lymphoma 2.2.2.1.10 Anaplastic large-cell lymphoma, T/null cell, primary systemic type 3. Patient requires treatment because NHL relapses following a response to standard chemotherapy or high dose chemotherapy + stem cell transplantation , or NHL is refractory (i.e. failure to achieve al least CR, PR or SD) to its more recent chemotherapy. 4. Prior autologous and/or allogeneic stem cell transplantation is allowed. In case of allogeneic hematopoietic stem cell transplantation (HSCT), patient has to be off immunosuppressive agents before he can enrolled. 5. Disease is measurable: existence of a bidimensional lesion greater than 2 cm in its longer diameter or malignant lymphocytosis greater than 5 x 10^9/L. Any other procedure for measurable disease in particular cases, could be allowed upon Pharma Mar’s approval. 6. Recovery from any non-hematological toxicity derived from previous treatments. The presence of alopecia and NCI-CTC grade < 2 symptomatic peripheral neuropathy is allowed. 7. Age >/= 18 years. 8. Performance status (ECOG) </= 2 (Appendix 2) 9. Adequate renal, hepatic, and bone marrow function (assessed </= 14 days before inclusion in the study): Neutrophil count >/= 1.5 x 10^9/L Platelet count >/= 100 x 10^9/L Haemoglobin >/= 8.0 g/dL Creatinine clearance >/= 40 ml/min (calculated from the Cockcroft and Gault formula, Appendix 3) Serum bilirubin </= 1.5 mg/dL and alkaline phosphatase </= 2.5 x ULN (</= 5 x ULN in case of extensive bone involvement) AST, ALT </= 2.5 x ULN (</= 5 x ULN in case of liver involvement). Albumin >/= 25 g/L. Lower haematological values due to bone marrow infiltration could be accepted upon Pharma Mar’s approval after clinical discussion between Pharma Mar and the Investigator. 10. Left ventricular ejection fraction within normal limits.

E.4

Principal exclusion criteria

1. Prior therapy with Aplidin. 2. Concomitant therapy with any anti-lymphoproliferative agent, including glucocorticoids at a daily dose greater than 10 mg prednisone or equivalent, except when they were indicated for symptom control and disease progression was documented while on esteroids. 3. Acute lymphoblastic leukemia. 4. CNS lymphoma. 5. HIV-associated lymphoma. 6. Prior gene therapy with viral vectors. 7. More than three previous lines of systemic biological agents or chemotherapies. (Bone marrow or stem cell transplantation as consolidation therapy of a previous response is understood as one line of chemotherapy). 8. Wash-out periods since the end of the precedent therapy less than: 6 weeks for nitroso-urea or high dose chemotherapy. 3 weeks for other chemotherapies or biological agents. 4 weeks for radiation or radionuclide therapy (6 weeks in case of prior extensive external beam radiation (more than 25% of bone marrow distribution). 4 weeks for major prior surgery. 30 days for any investigational product. 4 weeks for immunosuppressive therapy after allogeneic hematopoietic stem cell transplantation. 9. Pregnant or lactating women. 10. Men and women of reproductive potential who are not using effective contraceptive methods (one or more of the following): Complete abstinence from intercourse from 2 weeks prior to administration of the study drug, throughout the study, and for at least 6 months after completion or premature discontinuation from the study to account for elimination of the investigational drug; or, Patient or patient’s partner physical sterilization; or, One of the following, for female patients or female partner of male patients: Implants of levonorgestrel; or, Injectable progestogen; or, Oral contraceptive (combined or progestogen only; subject taking oral contraceptives should have been on a stable regimen for at least 2 months prior to screening),or, Any intrauterine device (IUD) with published data showing that the lowest expected failure rate is less than 1% per year (not all IUDs meet this criterion); or, Double barrier method (2 physical barriers or 1 physical barrier plus spermicide); or, Any other method with published data showing that the lowest expected failure rate for that method is less than 1% per year. 11. History of another neoplastic disease. The exceptions are: Non-melanoma skin cancer Carcinoma in situ of any site Any other cancer curatively treated and no evidence of disease for at least 10 years. 12. Known cerebral or leptomeningeal involvement. 13. Other relevant diseases or adverse clinical conditions: History or presence of unstable angina, myocardial infarction, valvular heart disease or congestive heart failure. Previous mediastinal radiotherapy. Uncontrolled arterial hypertension despite optimal medical therapy. Previous treatment with doxorubicin at cumulative doses in excess of 400 mg/m2. Symptomatic arrhythmia requiring treatment. Abnormal ECG (see Appendix 6). History of significant neurological or psychiatric disorders Active infection; infection by HIV, HBV or HCV o Myopathy or any clinical situation that causes significant and persistent elevation of CK (>2.5 ULN in two different determinations performed with one week appart) Significant non-neoplastic liver disease (e.g., cirrhosis, active chronic hepatitis) Uncontrolled endocrine diseases (e.g. diabetes mellitus, hypothyroidism or hyperthyroidism) (i.e. requiring relevant changes in medication within the last month, or hospital admission within the last 3 months). 14. Treatment with any investigational product in the 30 days period before inclusion in the study. 15. Known hypersensitivity to Aplidin, mannitol, cremophor EL, or ethanol 16. Limitation of the patient’s ability to comply with the treatment or follow-up protocol.

E.5 End points

E.5.1

Primary end point(s)

Objective response rate (CR/CRu+PR)

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

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

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Sopravvivenza, tossicita`

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

Yes

E.8.1.7.1

Other trial design description

Esplorativo

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

Information not present in EudraCT

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

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

6 mesi dopo l’ultima visita di trattamento per l’ultimo paziente in terapia (Follow-up massimo per lo studio)

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

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
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	Yes
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	4
F.4.2	For a multinational trial
F.4.2.1	In the EEA	56
F.4.2.2	In the whole clinical trial	58

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

2008-11-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-09-29

P. End of Trial
P.	End of Trial Status	Completed

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