| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
|
| E.1.3 | Condition being studied is a rare disease | No |
| 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) 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,
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 | Information not present in EudraCT |
| E.3 | Principal 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standing that consent may be withdrawn by the subject at any time without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
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 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. |
|
| 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 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. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| 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 | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 25 |
| 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 | No |
| 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
|
| There will be a long-term follow-up period with monthly visits until disease progression or relapse. Thereafter follow-up for survival will be continued by at least a phone call every other month. This will be done for all subjects until the last subject was treated and followed up for 1 year. |
|
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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