| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
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| 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 |
| The primary objective of this study is to determine the overall combined complete response rate [defined in this protocol as the combination of complete response (CR), including stringent CR [sCR]) and near CR (nCR)] following induction treatment with VELCADE (bortezomib), dexamethasone, and thalidomide (VDT) or VELCADE, dexamethasone, thalidomide, and cyclophosphamide (VDTC) in subjects with newly diagnosed symptomatic multiple myeloma who are candidates for high-dose therapy and stem cell transplantation (HDT/SCT). |
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| E.2.2 | Secondary objectives of the trial |
| To determine the overall combined CR rate, as defined above, post-HDT/SCT, To determine the: a) overall response rate (CR, very good partial response [VGPR], and partial response [PR]), b) sCR rate, both pre- and post-transplantation, c) time to response, and d) duration of response in each treatment group, To determine the time to disease progression (TTP) in each treatment group, To determine the progression-free survival (PFS), 1-year survival, and overall survival (OS) in each treatment group, To evaluate the safety and tolerability of VDT and VDTC, To determine the time to clinical relapse, To determine the feasibility of using immunophenotyping of bone marrow aspirates through flow cytometry as a technique to measure the extent of minimal residual disease (MRD) in subjects who have achieved a CR documented by standard techniques such as serum protein electrophoresis (SPEP), urine protein electrophoresis and immunofixation |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
| 1)Male or female between ≥18 and ≤70 years 2) Subject is a candidate for HDT combined with an autologous SCT 3) KPS score of ≥60% 4) Multiple myeloma diagnosed according to the following standard criteria3 AND requiring systemic therapy: Presence of M-component in serum and/or urine, plus clonal plasma cells in the bone marrow and/or a documented clonal plasmacytoma PLUS 1 or more of the following: – Calcium elevation (>11.5 mg/dL or >2.65 mmol/L) – Renal insufficiency (creatinine >2 mg/dL or >177 umol/L) – Anemia (hemoglobin <10 g/dL [<12.5 mmol/L] or at least 2 mg/dL [1.25 mmol/L] below normal) – Bone disease (lytic lesions or osteopenia) AND fulfill criteria for measurable disease, as defined by at least 1 of the following 3 measurements: VELCADE: Clinical Protocol 26866138-MMY-2043 FINAL – 27 April 2007 43 – Serum M-protein ≥1 g/dL (≥10 g/L) – Urine M-protein ≥200 mg/24 h – Serum free light chain (FLC) assay: Involved FLC level ≥10 mg/dL (≥100 mg/L) provided serum FLC ratio is abnormal Have pretreatment clinical laboratory values meeting the following criteria within 21 days before randomization: – Platelet count ≥70 x 109/L – Hemoglobin ≥8 g/dL (≥4.96 mmol/L) (prior red blood cell [RBC] transfusion or recombinant human erythropoietin use is allowed) – Absolute neutrophil count (ANC) ≥1.0 x 109/L – Aspartate aminotransferase (AST) ≤2.5 times the upper limit of normal – Alanine aminotransferase (ALT) ≤2.5 times the upper limit of normal – Total bilirubin ≤1.5 times the upper limit of normal, except in subjects with congenital bilirubinemia, such as Gilbert syndrome – Serum creatinine ≤2.5 mg/dL (≤220 μmol/L) – Corrected serum calcium <14 mg/dL (<3.5 mmol/L) Women of childbearing potential must agree to use 2 methods of contraception: 1 effective (for example hormonal or tubal ligation) and 1 barrier (for example latex condom, diaphragm) for at least 4 weeks before starting treatment, during the treatment phase, and for 4 weeks after the last dose [Please also refer to Section 1.5 and Section 4.4 for additional information]. Males must agree to use barrier contraception (latex condoms) when engaging in reproductive activity during the treatment phase and for 4 weeks after the last dose. [Please also refer to Section 1.5 and Section 4.4 for additional information]. Subjects (or their legally acceptable representatives) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study. To participate in the optional pharmacogenomic component of this study, subjects (or their legally acceptable representative) must have signed the informed consent form for pharmacogenomic research indicating willingness to participate in the pharmacogenomic component of the study. Refusal to consent for this component does not exclude a subject from participation in the clinical study. |
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| E.4 | Principal exclusion criteria |
| Diagnosis of smoldering OR non-secretory multiple myeloma or MGUS. Smoldering multiple myeloma is defined as asymptomatic multiple myeloma with absence of lytic bone lesions.52 MGUS is defined by presence of serum monoclonal protein <3 g/dL; absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the monoclonal protein; and (if determined) proportion of plasma cells in the bone marrow of 10% or less.53 Diagnosis of Waldenström’s disease or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions Prior or current systemic therapy for multiple myeloma including steroids (with exception of emergency use of a short course [maximum 4 days] of steroids before randomization or of prior or current use of bisphosphonates) Radiation therapy and/or plasmapheresis within 15 days before randomization History of allergic reaction attributable to compounds being given (VELCADE, thalidomide, dexamethasone, and/or cyclophoshamide) or compounds containing boron or mannitol Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 Uncontrolled or severe cardiovascular disease, including myocardial infarction, within 6 months of enrollment, New York Heart Association (NYHA) Class III or IV heart failure (see Attachment 3), uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis Concurrent medical condition or disease (e.g., active systemic infection, uncontrolled diabetes) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study Use of any investigational drugs within 30 days before randomization Pregnant or lactating women: A serum β-hCG pregnancy test must be performed at the Screening visit for female subjects of childbearing potential. In the event that a site is unable to obtain the results of a serum pregnancy test in a timely manner, a urine pregnancy test may be substituted. If the test is positive, the subject must be excluded from the study. Confirmation that the subject is not pregnant must be established |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is overall combined complete response rate in the response evaluable population. CR is a valid endpoint for a Phase II study designed to determine the optimal induction regime in a subject population with MM for whom HDT/SCT has become the standard of care, as it will yield a determination in a reasonable amount of time. Furthermore, post induction rates of CR/nCR have been demonstrated to be a good surrogate marker for long-term benefit and survival in this subjects population |
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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 | No |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Information not present in EudraCT |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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