Clinical Trials Register

Summary
EudraCT Number:	2008-003213-27
Sponsor's Protocol Code Number:	26866138MMY3022
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-08-25
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

Germany - BfArM

A.2

EudraCT number

2008-003213-27

A.3

Full title of the trial

Randomized Phase III Study on Bortezomib and Low-Dose Dexamethasone with or without Continuous Low-Dose Oral Cyclophosphamide for Primary Refractory or Relapsed Multiple Myeloma

A.3.1

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

Comparison of two strategies to treat refractory or relapsed Multiple Myeloma. All patients receive Bortezomib and Dexamethasone, one half receives additional Cyclophosphamide.

A.3.2

Name or abbreviated title of the trial where available

VelKom

A.4.1

Sponsor's protocol code number

26866138MMY3022

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	ORTHO BIOTECH, Division of JANSSEN-CILAG GmbH
B.1.3.4	Country	Germany
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	ORTHO BIOTECH Division of Janssen-Cilag GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ORTHO BIOTECH Division of Janssen-Cilag GmbH
B.5.2	Functional name of contact point	Projektleiter Dr. Carsten Gerdemann
B.5.3	Address:
B.5.3.1	Street Address	Johnson & Johnson Platz 1
B.5.3.2	Town/ city	Neuss
B.5.3.3	Post code	41470
B.5.3.4	Country	Germany
B.5.4	Telephone number	00492137955 242
B.5.5	Fax number	00492137955488
B.5.6	E-mail	cgerdema@its.jnj.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	VELCADE 3,5 mg Pulver zur Herstellung einer Injektionslösung
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.3.2	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	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent)
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.3.9.3	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 to mg
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	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	Endoxan
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxter Oncology GmbH, Kantstr. 2, 33790 Halle
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.3.1	Product name	cyclophosphamide
D.3.4	Pharmaceutical form	Coated 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	CYCLOPHOSPHAMIDE
D.3.9.1	CAS number	50180
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	50
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: 3
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	Fortecortin 4 mg Tabletten
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Pharma GmbH, Alsfelder Str. 17, 64289 Darmstadt
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.3.1	Product name	dexamethasone
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	50022
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

Refractory or relapsed multiple myeloma after 1 to 3 previous lines of therapy, including high-dose therapy

E.1.1.1

Medical condition in easily understood language

Refractory or relapsed multiple myeloma after 1 to 3 previous lines of therapy, including high-dose therapy

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10028228
E.1.2	Term	Multiple myeloma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Determination of efficacy as time to progression of the standard therapy of bortezomib and low dose dexamethasone in combination with or without continuous low dose oral cyclophosphamide in patients with primary refractory or relapsed myeloma (1st - 3rd relapse).

E.2.2

Secondary objectives of the trial

Determination of
· overall survival
· progression free survival
· best response rate according to IMWG 2006 criteria
· safety
· change in Karnofsky Performance Status Score and the quality of life by EQ-5D
questionnaire
· the health economic impact by rate of skeletal related events (SRE) and necessity
for dialysis due to renal insufficiency

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female ≥18 years of age
2. Informed consent
3. Diagnosis of multiple myeloma and measurable disease (serum M-protein
≥1g/dL (10g/L, urine light-chain excretion ≥200mg/24h, involved FLC level
≥10mg/dL provided sFLC ratio is abnormal)
4. Relapse or refraction of multiple myeloma following 1-3 previous lines of therapy and requires treatment. The subject has undergone or is not eligible for bone marrow transplantation.
5. Karnofsky status ≥60%
6. Life expectancy estimated at screening of at least 6 months
7. Willingness or ability to comply in the investigator's opinion
8. Women must be postmenopausal or surgically sterilized; women of childbearing
potential must use a safe method of contraception before entry and throughout
the study and have a negative pregnancy test at screening. Accepted is also a
male partner vasectomized
9. Male patients must use a reliable method of contraception from screening up to
6 months after trial completion.

E.4

Principal exclusion criteria

1. More than three previous lines of therapy for multiple myeloma
2. Known allergy or hypersensitivity to bortezomib, dexamethasone and/or cyclo-
phosphamide or to any of the constituent compounds containing boron, mannitol,
or lactose
3. Progressive disease or stable disease under bortezomib in a previous line of
therapy
4. Oligosecretory or non-secretory multiple myeloma
5. Reception of nitrosoureas or any other chemotherapy within 6 weeks before
enrolment
6. Reception of corticosteroids (>10 mg/day prednisone or equivalent) within 3
weeks before enrolment
7. Immunotherapy or antibody therapy for multiple myeloma within 8 weeks
before enrolment (Ig substitution therapy is not excluded)
8. Plasmapheresis within 2 weeks before enrolment
9. Major surgery within 4 weeks before enrolment (kyphoplasty is not considered
major surgery)
10. Peripheral neuropathy or neuropathic pain of grade 2 or greater intensity, as
defined by NCI CTCAE, version 3.0
11. Uncontrolled or severe cardiovascular disease, including myocardial infarction
within 6 months before enrolment or NYHA Class III or IV heart failure, uncon-
trolled angina, acute diffuse infiltrative pulmonary and pericardial disease,
severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of
acute ischemia, active conduction system abnormalities or cardiac amyloidosis
12. Clinically relevant or poorly controlled vascular, pulmonary, gastrointestinal,
endocrine, neurological, psychiatric or metabolic diseases, which could potentially
interfere with the completion of treatment according to protocol
subject has urinary tract obstruction or cystitis before start of therepy
Subject has liver or renal insufficiency indicated by one or more of the following
pre-treatment laboratory values within 14 days before and at baseline:
· platelet count < 50×109/L (transfusion support within 14 days before the test
is not allowed)
· haemoglobin ≤ 7,5 g/dL
· calculated or measured creatinine clearance < 20 mL/min
· absolute neutrophil count (ANC) < 0,75×109/L (the use of colony stimulating
factors within 14 days before the test is not allowed)
· adjusted serum calcium ≥14 mg/dL (3,5 mmol/L)
· aspartate transaminase (AST) > 2,5 × the upper limit of normal (ULN)
· alanine transaminase (ALT) > 2,5 × ULN
· total bilirubin > 1,5 × ULN
13. Malignancy other than multiple myeloma within 5 years before enrolment:
Exceptions for the following if treated and not active: basal cell or nonmetastatic
squamous cell carcinoma of the skin, cervical carcinoma in situ or FIGO Stage 1 of
the cervix
14. HIV positive status. When assessed by the investigator to be at risk for HIV
testing in accordance with local policies
15. Positive status of hepatitis B surface antigen or known active hepatitis C. When
assessed by the investigator to be at risk for hepatitis B or C testing in
accordance with local regulations
16. Systemic infection requiring treatment
17. Use of disallowed concomitant medication
18. Participation in other clinical studies conducted in parallel and participation in a
clinical study, i.e. subject has received an experimental drug or used an ex-
perimental medical device, within 30 days prior to enrolment in this study. This
does not exclude long-term follow-up periods without drug treatment of previous
studies.
19. Pregnancy or breast-feeding status
20. Previously enrolment in this study
21. Personal or financial dependence on the investigator or the institution con-
ducting the study
22. Currently known known alcohol and drug abuse and/or
dependence

E.5 End points

E.5.1

Primary end point(s)

Time to progression (TTP), defined as time from randomisation to first observation of disease progression, censoring for death or drop out without progression.
Patients who died or dropped out due to any other reason without progression will be censored with the day of death or drop-out, respectively. Patients who are alive at the end of the study and have no progression will be censored with the last available date.
For review of the primary endpoint a central expert panel will be implemented.

E.5.1.1

Timepoint(s) of evaluation of this end point

defined as time from randomisation to first observation of disease progression, censoring for death or drop out without progression

E.5.2

Secondary end point(s)

Overall survival, Progression free survival, Best response rate according to IMWG criteria, Safety parameters, Change in Karnofsky Index from baseline to EoT, Quality of life assessed by EQ-5D, Rate of sceletal related events, Rate of necessity for dialysis due to renal insufficiency

E.5.2.1

Timepoint(s) of evaluation of this end point

study end, End of Treatmenmt

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)

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

combination of bortezomib and dexamethasone with or without cyclophosphamide

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

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

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

Last visit of last subject

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:

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

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

270

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)

After patients have completed treatment according to the protocol there will be a follow-up phase without treatment. VELCADE is commercially available. It lies in the discretion of the investigator to decide to administer another course with VELCADE in case of relapse.

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

2008-11-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-11-07

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2013-01-08

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