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 - PAD versus VAD in 2nd line multiple myeloma

• Register: EUCTR
• Last refreshed on: 28 January 2013
• Main ID: EUCTR2006-001709-27-DE
• Date of registration: 07/07/2006
• Prospective Registration: Yes
• Primary sponsor: Janssen-Cilag International NV
• Public title: 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 - PAD versus VAD in 2nd line multiple myeloma
• Scientific title: 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 - PAD versus VAD in 2nd line multiple myeloma
• Date of first enrolment: 05/10/2006
• Target sample size: 212
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-001709-27
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no

Countries of recruitment

Germany, Hungary, Lithuania

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female subject, aged 18 years and more.
2. The subject has given voluntary written informed consent before performance of
any study related procedure not part of normal medical care, with the under-
standing that consent may be withdrawn by the subject at any time without
prejudice to future medical
care.
3. Subject was previously diagnosis of 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 0,5 g/dl immunoglobulin A (IgA)) or urine light-chain
excretion of 200 mg or more in 24 hours.
4. The subject has relapsed or refractory multiple myeloma following 1 previous line
of therapy and 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:
- >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.
- 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% or more.
6. Subject has a fife-expectancy 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 drug administration):
- Platelet count >=50 x 10 9/l.
- Hemoglobin of 7,5 g/dl or more without transfusion support within 7 days
before the test.
- Creatinine clearance 20 ml/minute or more .
- Absolute neutrophil count (ANC) >=0,75 x 10 9/l without the use of colony
stimulating factors.
- Adjusted serum calcium <14 mg/dl (3,5 mmol/l).
- Aspartate aminotransferase (AST) 2,5 x the upper limit of normal (ULN) or less.
- Alanine aminotransferase (ALT) 2,5 x the ULN or less.
- Total bilirubin 1,5 x the ULN or less.
8. The subject is , in the investigator's 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 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 contra-
ception from screening through at least 30 days after completion of the last
tre
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 is 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 (NCICTCAE), version 3.0.
11. Subject had a myocardial infarction within 6 months of enrolment or 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 regulations.)
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.
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 sub-
ject 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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Multiple myeloma
MedDRA version: 8.1 Level: LLT Classification code 10028228 Term: Multiple myeloma

Intervention(s)

Trade Name: VELCADE 3,5 mg Pulver zur Herstellung einer Injektionslösung
Product Code: PS-341, 26866138-AAA-PB-001
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: bortezomib
CAS Number: 179324-69-7
Current Sponsor code: 26866138
Other descriptive name: Boronic Acid: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2[(pyrazinylcarbonyl)amino]propyl]amino]butyl
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 3,5-

Product Name: vincristine
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Vincristine sulfate
CAS Number: 2068-78-2
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-mg/ml

Product Name: doxorubicin or adriamycin
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: Doxorubicin hydochloride
CAS Number: 25316-40-9
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-

Primary Outcome(s)

Secondary Objective: To assess
the duration of response,
event free survival,
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.

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 alpha = 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.

Main Objective: To assess the safety and efficacy of replacing vincristine with Velcade® (bortezomib) 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.

Secondary ID(s)

2006-001709-27-LT

26866138-MMY-2038