| 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 | 9.1 |
| 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 |
| The primary objective is to assess the efficacy of adding either Cyclophosphamide or Lenalidomide to the combination of Velcade® (bortezomib) and Dexamethasone in subjects with multiple myeloma who are refractory to or have relapsed/progressed after their primary therapy for multiple myeloma and once enrolled in this study have achieved a stable disease response after four cycles of Velcade® and Dexamethasone. The efficacy response will be measured by the response rate of the disease. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives include assessment of the safety profile and additional efficacy parameters including the time to response, duration of response, progression free survival, the time to progression, the one year survival and the overall survival of the subjects treated with Velcade® in combination with Dexamethasone (VD) or Velcade® in combination with Dexamethasone and Cyclophosphamide (VDC) or Velcade® in combination with Dexamethasone and Lenalidomide (VDL). Change in renal function after the four initial cycles of Velcade® in combination with Dexamethasone (VD) will be also evaluated. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subject, aged ≥18 years.
2. The subject has relapsed/progressed or is refractory for multiple myeloma following 1 previous line of therapy.
Progressive Disease (PD) or relapse are defined as one or more of the following criteria:
Criteria for PD:
•>25% increase from lowest response level in serum M-component and/ or (the absolute increase must be > 0.5 g/dl)
•>25% increase from lowest response level in urine M-component and/or (the absolute increase must be > 200 mg/24 h);
•Bone marrow plasma cell percentage: the absolute % must be > 10%;
•Definite development of new bone lesion or soft-tissue plasmacytomas or definite increase in size of existing bone lesion or soft-tissue plasmacytomas;
•Development of hypercalcemia (corrected serum calcium >11.5 mg/dl or 2.65 mmol/l) that can be attributed solely to the plasma cell proliferative disorder.
Criteria for relapse from CR
•Reappearance of serum or urine M-protein by immunofixation or electrophoresis
•Development of >5% plasma cells in bone marrow
•Appearance of any other sign of progression (i.e., new lytic bone lesion or new plasmacytomas or hypercalcemia).
All relapse categories require two consecutive assessments made at anytime before classification as relapse or disease progression.
3. Measurable secretory multiple myeloma: measurable disease for secretory multiple myeloma is defined by at least one of the following measurements: serum monoclonal protein greater than or equal to 1 g/dl (> 10 gm/l) [10g/l], urine M-protein of ≥200 mg/24 hours.
4. Subject has a Karnofsky performance status of ≥60.
5. Subject has a life expectancy estimated at screening of at least 6 months.
6. The subject meets the following pretreatment laboratory criteria at and within 14 days before baseline (Day 1 of Cycle 1, before study drug administration):
•Platelet count ≥50x 109/L without transfusion support within the 7 days before the test
•Hemoglobin ≥ 7.5 g/dL without transfusion support within the 7 days before the test
•Absolute neutrophil count (ANC) ≥0.75 x 10^9/L without the use of colony stimulating factors within 14 days before the test
•Corrected serum calcium < 14 mg/dL (3.5 mmol/L).
•Aspartate transaminase (AST): ≤2.5 x the upper limit of normal (ULN).
•Alanine transaminase (ALT): ≤2.5 x ULN.
•Total bilirubin: ≤1.5 x ULN.
7. The subject is, in the investigator’s opinion, willing and able to comply with the protocol requirements.
8. The subject has given 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 his or her medical care.
9. If female, the subject is either postmenopausal or surgically sterilised or willing to use an acceptable method of birth control (i.e., total abstinence – periodic abstinence can not be allowed, a hormonal contraceptive, intrauterine device, diaphragm with spermicide, or condom with spermicide) from screening through six months following treatment.
10. If male, the subject agrees to use an acceptable barrier method for contraception from screening through six months following treatment. |
|
| 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, Dexamethasone and/or Cyclophosphamide and/or Lenalidomide or any of the constituents compounds such as boron, mannitol, or lactose.
3.Subject has oligosecretory or non-secretory multiple myeloma.
4.Subject received nitrosoureas or any other chemotherapy (including thalidomide), clarithromycin, interferon within 6 weeks before enrolment. Note: subjects can have received thalidomide or interferon as mantainance therapy, according to local standard of care.
5.Subject received corticosteroids (> 10 mg/day prednisone or equivalent) within 3 weeks before enrolment. Note: subjects can have received steroids (dexamethasone or equivalent) as mantainance therapy according to local standard of care. In addition, subjects can have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy within 3 weeks prior to study entry.
6.Subject received immunotherapy or antibody therapy within 8 weeks before enrolment.
7.Subject received plasmapheresis within 2 weeks before enrolment.
8.Subject had major surgery within 4 weeks before enrolment (kyphoplasty was not considered major surgery).
9.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 (NCI CTCAE), version 3.0.
10.Subject had a myocardial infarction within 6 months of enrolment or has 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.
11.Subject has poorly controlled hypertension, diabetes mellitus, or other serious medical condition (such as severe hepatic imparment, pericardial disease, acute diffuse infiltrative pulmonary disese, systemic infections etc) or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol.
12.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.
13.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 policies.
14.Subject is known to be hepatitis B surface antigen-positive or has 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.)
15.Subject has an active systemic infection requiring treatment.
16.Subject uses disallowed medication
17.Subject has received an experimental drug or used an experimental medical device within 4 weeks before enrolment.
18.If female, the subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative pregnancy test at screening. Pregnancy testing is not required for postmenopausal or surgically sterilised women.
see section 9.3 of the protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy criterion will be the best response during the treatment period as referenced by the IMWG 2006 criteria (see Attachment 5: Disease Response Criteria). To have a positive response, the subject should have CR, VGPR or PR. The categories of stringent CR and clinical relapse (not applicable to assess efficacy end-points) are not used in the study.
Response will be evaluated after each treatment cycle and every follow up visit until disease progression or relapse from CR.
Secondary endpoints:
•Changes in renal function after 4 cycles of VD treatment – Calculated Glomerular Filtration rate
•Time to Response: time from start of treatment to the date of the first documentation of a confirmed response
•Time to progression (TTP): Time from start of treatment to disease progression or relapse from CR, with deaths owing to causes other than progression not counted, but censored.
•Duration of response (DOR): Applies to subjects achieving at least PR and is measured from start of achieving PR (first observation) to the time of disease progression or relapse from CR, with deaths owing to causes other than progression not counted, but censored.
•Progression free survival (PFS): Time from start of the treatment to disease progression, relapse from CR or death.
•One-year survival: the subject survival probability at 1 year after start of treatment.
•Overall survival: the time from start of treatment to the date of death
To estimate these efficacy end-points, disease progression and relapse is defined as follows:
•>25% increase from baseline in serum M-component and/ or (the absolute increase must be > 0.5 g/dl) or urine M-component and/or (the absolute increase must be > 200 mg/24 h);
•Bone marrow plasma cell percentage: the absolute % must be > 10%;
•Definite development of new bone lesion or soft-tissue plasmacytomas or definite increase in size of existing bone lesion or soft-tissue plasmacytomas;
•Development of hypercalcemia (corrected serum calcium >11.5 mg/dl or 2.65 mmol/l) that can be attributed solely to the plasma cell proliferative disorder.
All relapse categories require two consecutive assessments made at anytime before classification as relapse or disease progression.
see section 9.3 of the protocol |
|
| 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 | No |
| 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) | 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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 52 |
| 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
| |
| 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 | 48 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 48 |
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