| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of myeloma patients progressing or relapsing after autologous transplantation |
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| MedDRA Classification |
| 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 |
| Test the hypothesis that treatment with Velcade plus Thalidomide plus Dexamethasone in combination, will result in a longer time to progression (TTP) than Thalidomide plus Dexamethasone in subjects with relapsed or progressive myeloma after autologous transplantation |
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| E.2.2 | Secondary objectives of the trial |
| Compare the treatment groups for : overall survival; response rate (complete + partial + minimal) using standard criteria and treatment related complications. |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
•Male or female and at least 18 years-of-age
•Histologically confirmed diagnosis of multiple myeloma with evaluable disease parameters (see attachment, Criteria for the diagnosis of myeloma)
•Relapsing or having a progressive disease after an autologous transplantation as defined by Bladé et al criteria (section 8.2) :
•Relapse as defined by one of the following:
1.Reappearance of serum or urinary paraprotein in immunofixation or routine electrophoresis, confirmed by at least one further investigation and excluding oligoclonal immune reconstitution.
2.>5% plasma cells in a bone marrow aspirate or on trephine bone biopsy
3.Development of new lytic bone lesions or soft tissue plasmacytomas or definite increase in the size of residual bone lesions. Development of a compression fracture does not exclude response.
4.Development of hypercalcemia, corrected serum calcium >11.5mg/dL or 2.8 mmol/L, that is not attributable to any other cause
•Progressive disease as defined by one of the following:
-1/ > 25% increase in the level of the serum monoclonal paraprotein (5 g/l increase minimum and at least two investigations)
-2/ > 25% increase in the 24 h urinary light chain excretion (200 mg/d increase minimum and at least two investigations)
-3/ > 25% increase in plasma cells in a bone marrow aspirate (absolute increase of at least 10%)
-4/ increase in the size of existing bone lesions or soft tissue plasmacytomas
-5/ new bone lesions or soft tissue plasmacytomas
-6/ onset of hypercalcemia not attributable to any other cause
•Measurable disease defined as: quantifiable serum monoclonal antibody defined as a serum monoclonal protein >1g/dL for IgG, or >0.5g/dL for IgA
•Karnofsky performance status > 50 %
•Life expectancy of at least 3 months
•Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (ie, a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.. Male subject agrees to use an acceptable method for contraception for the duration of the study.
•Negative serum or urine β-HCG pregnancy test at screening for subjects of child-bearing potential
•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 future medical care.
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| E.4 | Principal exclusion criteria |
•Patients with non-secretory MM
•Karnofsky performance status < or equal to 50%
•Patient has a platelet count < 40,000 109/L within 14 days before enrollment.
•Patient has an absolute neutrophil count <1.0 109/L within 14 days before enrollment.
•Patient has a calculated or measured creatinine clearance <30 mL/minute within 14 days before enrollment.
•Patient has Grade 2 peripheral neuropathy within 14 days before enrollment.
•Seropositive for HIV, or active hepatitis A, B or C infection
•Patient has hypersensitivity to bortezomib, boron or mannitol.
•Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum -human chorionic gonadotropin (-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
•Patient has received other investigational drugs with 14 days before enrollment
•Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
•Previous or concurrent malignancies at other sites, with the exception of appropriately treated localized epithelial skin or cervical cancer. Patients with remote histories (>5 years) of other cured tumors may be entered
•Poorly controlled hypertension or diabetes mellitus or other serious medical or psychiatric conditions that could interfere with adherence to or completion of this study
•Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrollment, New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint
The primary endpoint of this study is time to progression (TTP): the interval between the date of randomization and the date of disease progression. Death without documented progression will be treated as a competing risk for curve estimation purposes and as a censoring event for significance testing in the framework of the Cox proportional hazards model. Subjects who are progression-free at the time of data cutoff for an analysis or are lost to follow-up will be censored for TTP at the time of their last tumor assessment. The date of progressive disease (PD) will be determined as the date of the first indication of progression using the EBMT criteria.
Secondary endpoints
The secondary endpoints of this study are response rate and overall survival.
Response rate is defined as the proportion of subjects who achieve a complete, partial or minimal response according to the criteria set out in the appendices 8.3.
Overall survival (OS) is defined as the interval between the date of randomization and the subject’s death from any cause. If the date of death is unknown, the data will be censored at the date that the subject is last known to have been alive.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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.8.5 | 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 |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
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| Treatment will continue until disease progression, or the occurrence of unacceptable treatment-related toxicity, or up to a total of 12 cycles of Velcade except for those subjects who have a continuing decrease in the levels of paraprotein after 12 cycles. These subjects may continue for as long as treatment is tolerated, and they continue to respond. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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