Clinical Trials Register

Summary
EudraCT Number:	2006-001709-27
Sponsor's Protocol Code Number:	26866138MMY2038
National Competent Authority:	Lithuania - SMCA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2006-06-29
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

Lithuania - SMCA

A.2

EudraCT number

2006-001709-27

A.3

Full title of the trial

A Phase 2, Multicentre, Randomised, Open-Label, Parallel Group Study to Evaluate the Safety and Efficacy of Velcade® when added to Adriamycin-Dexamethasone Treatment versus Vincristine-Adriamycin-Dexamethasone Standard Treatment in Subjects with Multiple Myeloma who are Refractory to or Have Relapsed after Primary Therapy for Multiple Myeloma.

A.3.2

Name or abbreviated title of the trial where available

PAD versus VAD in 2nd line multiple myeloma

A.4.1

Sponsor's protocol code number

26866138MMY2038

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	Janssen-Cilag International N.V.
B.1.3.4	Country	Belgium
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	VELCADE
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag International N.V.
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	VELCADE 3.5 mg powder for solution for injection
D.3.2	Product code	PS-341, 26866138-AAA-PB-001
D.3.4	Pharmaceutical form	Powder for solution for injection
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	bortezomib
D.3.9.1	CAS number	179324-69-7
D.3.9.2	Current sponsor code	26866138
D.3.9.3	Other descriptive name	Boronic Acid: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2[(pyrazinylcarbonyl)amino]propyl]amino]butyl
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	3.5
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

Multiple Myeloma

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.0
E.1.2	Level	LLT
E.1.2	Classification code	10028228

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the safety and efficacy of replacing vincristine with Velcade® (bortezomib, also named PS341) in the standard therapy vincristine, adriamycin and dexamethasone (VAD) in subjects with multiple myeloma who are refractory to or have relapsed after their primary therapy for multiple myeloma. The efficacy response will be measured by the response rate of the disease.

E.2.2

Secondary objectives of the trial

To assess the duration of response, event free survival, the time to progression, the one year survival and the overall survival of the subjects treated with Velcade® in combination with the adriamycin and dexamethasone (PAD) therapy versus the VAD standard therapy.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female subject, aged >= 18 years.
2. The subject has given voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to his or her medical care.
3. Subject was previously diagnosed with multiple myeloma based on standard criteria and has measurable disease. Measurable disease for secretory multiple myeloma is defined as any quantifiable serum monoclonal protein value (generally, but not exclusively, greater than 1 g/dL of immunoglobulin G (IgG) M-Protein and greater than 0.5g/dL immunoglobulin A (IgA)) or urine light-chain excretion of e 200 mg/24 hours.
4. The subject has relapsed or is refractory for multiple myeloma following 1 previous line of therapy and is scheduled by the investigator to be treated with vincristine, adriamycin and dexamethasone (VAD) combination treatment. PD or relapse are defined as one or more of the following criteria:
Criteria for PD:
Criteria for PD for subjects not in CR
·>25% increase in either serum or urine M-protein;
·>25% increase in plasma cells on bone marrow;
·Definite increase in size of bone lesion or plasmacytoma;
·Development of new bone lesion or plasmacytoma; or
·Development of hypercalcemia (corrected serum calcium >11.5 mg/dl or 2.8 mmol/l) not attributable to other causes.
Criteria for relapse from CR
·reappearance of serum or urinary paraprotein on immunofixation or routine electrophoresis, confirmed by at least one further investigation and excluding oligoclonal immune reconstitution
·>5% plasma cells in bone marrow aspirate or on trephine bone biopsy
·Development of new lytic bone lesions or soft tissue plasmacytomas or definite increase in the size of residual bone lesions
·Development of hypercalcemia (corrected serum calcium >11,5 mg/dl or 2.8 mmol/l) not attributable to any other cause.
5.Subject has a Karnofsky performance status of >= 60 (see Attachment 1: Karnofsky Performance Status Scale).
6. Subject has a life expectancy estimated at screening of at least 6 months.
7. The subject meets the following pretreatment laboratory criteria at and within 14 days before baseline (Day 1 of Cycle 1, before study drug administration):
-platelet count >= 50x 109/L;
-haemoglobin >7.5 g/dl without transfusion support within 7 days before the test;
-creatinine clearance >= 20 mL/min (calculated or measured, see Attachment 2: Creatinine Clearance Calculation for formula).
-absolute neutrophil count (ANC) >= 0.75 x 10 9/L without the use of colony stimulating factors.

-corrected serum calcium < 14 mg/dL (3.5 mmol/L).
-aspartate transaminase (AST): <= 2.5 x the upper limit of normal (ULN).
-alanine transaminase (ALT): <= 2.5 x ULN.
-total bilirubin: <= 1.5 x ULN.
8. The subject is, in the investigators opinion, willing and able to comply with the protocol requirements.
9. If female, the subject is either postmenopausal or surgically sterilised or willing to use an acceptable method of birth control (i.e., total abstinence periodic abstinence can not be allowed-, a hormonal contraceptive, intrauterine device, diaphragm with spermicide, or condom with spermicide) from screening through at least 30 days after completion of the last treatment cycle.
10. If male, the subject agrees to use an acceptable barrier method for contraception from screening through at least 30 days after completion of the last treatment cycle.

E.4

Principal exclusion criteria

1. Subject received more than one previous line of therapy for multiple myeloma.
2. Subject has known allergy or hypersensitivity to bortezomib, boron or mannitol.
3. Use of Velcade® in the previous line of therapy and/or the subject received Velcade® in a previous trial.
4. Subject has oligosecretory or non-secretory multiple myeloma.
5. Subject received nitrosoureas or any other chemotherapy (including thalidomide), clarithromycin, interferon within 6 weeks.
6. Subject received corticosteroids (> 10 mg/day prednisone or equivalent) within 3 weeks before enrolment.
7. Subject received immunotherapy or antibody therapy within 8 weeks before enrolment.
8. Subject received plasmapheresis within 4 weeks before enrolment.
9. Subject had major surgery within 4 weeks before enrolment (kyphoplasty was not considered major surgery).
10. Subject has peripheral neuropathy or neuropathic pain of grade 2 or greater intensity, as defined by the National Cancer Institute Common Terminology Criteria of Adverse Events (NCI CTCAE), version 3.0 (see Attachment 6 for link).
11. Subject had a myocardial infarction within 6 months of enrolment or had New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
12. Subject has poorly controlled hypertension, diabetes mellitus, or other serious medical or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol.
13. Subject was treated for a cancer other than multiple myeloma within 5 years before enrolment, with the exception of basal cell carcinoma or cervical cancer in situ.
14. Subject is known to be human immunodeficiency virus (HIV)-positive. Subjects assessed by the investigator to be at risk for HIV infection should be tested in accordance with local policies.
15. Subject was known to be hepatitis B surface antigen-positive or had known active hepatitis C infection. (Subjects assessed by the investigator to be at risk for hepatitis B or C infection are to be tested in accordance with local regulations.)
16. Subject had an active systemic infection requiring treatment.
17. Subject uses disallowed medication (see section 8.2).
18. Subject has received an experimental drug or used an experimental medical device within 4 weeks before enrolment.
19. If female, the subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum pregnancy test at screening. Pregnancy testing is not required for postmenopausal or surgically sterilised women.

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint is Response Rate as defined by the combination of subjects with CR and PR according to the EBMT (European Group for Blood and Marrow Transplantation) criteria. It will be analysed by a stratified Mantel-Hanszel test at a 2-sided level where a = 5%. The stratification variables will be primary therapy (high dose versus conventional dose therapy and whether or not stem cells were transplanted), age groups and country.
The primary analysis will be based on the best response obtained during the treatment period.
Subjects who discontinue the treatment period without reaching a PR or CR will be analysed as non-responders.

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

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

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

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.8.6 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

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

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	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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2006-06-29.	Yes
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	30
F.4.2	For a multinational trial
F.4.2.1	In the EEA	195
F.4.2.2	In the whole clinical trial	212

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

2006-09-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2006-07-17

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2008-01-18

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