E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Refractory or relapsed multiple myeloma after 1 to 3 previous lines of therapy, including high-dose therapy |
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E.1.1.1 | Medical condition in easily understood language |
Refractory or relapsed multiple myeloma after 1 to 3 previous lines of therapy, including high-dose therapy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Determination of efficacy as time to progression of the standard therapy of bortezomib and low dose dexamethasone in combination with or without continuous low dose oral cyclophosphamide in patients with primary refractory or relapsed myeloma (1st - 3rd relapse). |
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E.2.2 | Secondary objectives of the trial |
Determination of · overall survival · progression free survival · best response rate according to IMWG 2006 criteria · safety · change in Karnofsky Performance Status Score and the quality of life by EQ-5D questionnaire · the health economic impact by rate of skeletal related events (SRE) and necessity for dialysis due to renal insufficiency
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female ≥18 years of age 2. Informed consent 3. Diagnosis of multiple myeloma and measurable disease (serum M-protein ≥1g/dL (10g/L, urine light-chain excretion ≥200mg/24h, involved FLC level ≥10mg/dL provided sFLC ratio is abnormal) 4. Relapse or refraction of multiple myeloma following 1-3 previous lines of therapy and requires treatment. The subject has undergone or is not eligible for bone marrow transplantation. 5. Karnofsky status ≥60% 6. Life expectancy estimated at screening of at least 6 months 7. Willingness or ability to comply in the investigator's opinion 8. Women must be postmenopausal or surgically sterilized; women of childbearing potential must use a safe method of contraception before entry and throughout the study and have a negative pregnancy test at screening. Accepted is also a male partner vasectomized 9. Male patients must use a reliable method of contraception from screening up to 6 months after trial completion.
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E.4 | Principal exclusion criteria |
1. More than three previous lines of therapy for multiple myeloma 2. Known allergy or hypersensitivity to bortezomib, dexamethasone and/or cyclo- phosphamide or to any of the constituent compounds containing boron, mannitol, or lactose 3. Progressive disease or stable disease under bortezomib in a previous line of therapy 4. Oligosecretory or non-secretory multiple myeloma 5. Reception of nitrosoureas or any other chemotherapy within 6 weeks before enrolment 6. Reception of corticosteroids (>10 mg/day prednisone or equivalent) within 3 weeks before enrolment 7. Immunotherapy or antibody therapy for multiple myeloma within 8 weeks before enrolment (Ig substitution therapy is not excluded) 8. Plasmapheresis within 2 weeks before enrolment 9. Major surgery within 4 weeks before enrolment (kyphoplasty is not considered major surgery) 10. Peripheral neuropathy or neuropathic pain of grade 2 or greater intensity, as defined by NCI CTCAE, version 3.0 11. Uncontrolled or severe cardiovascular disease, including myocardial infarction within 6 months before enrolment or NYHA Class III or IV heart failure, uncon- trolled angina, acute diffuse infiltrative pulmonary and pericardial disease, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia, active conduction system abnormalities or cardiac amyloidosis 12. Clinically relevant or poorly controlled vascular, pulmonary, gastrointestinal, endocrine, neurological, psychiatric or metabolic diseases, which could potentially interfere with the completion of treatment according to protocol subject has urinary tract obstruction or cystitis before start of therepy Subject has liver or renal insufficiency indicated by one or more of the following pre-treatment laboratory values within 14 days before and at baseline: · platelet count < 50×109/L (transfusion support within 14 days before the test is not allowed) · haemoglobin ≤ 7,5 g/dL · calculated or measured creatinine clearance < 20 mL/min · absolute neutrophil count (ANC) < 0,75×109/L (the use of colony stimulating factors within 14 days before the test is not allowed) · adjusted serum calcium ≥14 mg/dL (3,5 mmol/L) · aspartate transaminase (AST) > 2,5 × the upper limit of normal (ULN) · alanine transaminase (ALT) > 2,5 × ULN · total bilirubin > 1,5 × ULN 13. Malignancy other than multiple myeloma within 5 years before enrolment: Exceptions for the following if treated and not active: basal cell or nonmetastatic squamous cell carcinoma of the skin, cervical carcinoma in situ or FIGO Stage 1 of the cervix 14. HIV positive status. When assessed by the investigator to be at risk for HIV testing in accordance with local policies 15. Positive status of hepatitis B surface antigen or known active hepatitis C. When assessed by the investigator to be at risk for hepatitis B or C testing in accordance with local regulations 16. Systemic infection requiring treatment 17. Use of disallowed concomitant medication 18. Participation in other clinical studies conducted in parallel and participation in a clinical study, i.e. subject has received an experimental drug or used an ex- perimental medical device, within 30 days prior to enrolment in this study. This does not exclude long-term follow-up periods without drug treatment of previous studies. 19. Pregnancy or breast-feeding status 20. Previously enrolment in this study 21. Personal or financial dependence on the investigator or the institution con- ducting the study 22. Currently known known alcohol and drug abuse and/or dependence
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to progression (TTP), defined as time from randomisation to first observation of disease progression, censoring for death or drop out without progression. Patients who died or dropped out due to any other reason without progression will be censored with the day of death or drop-out, respectively. Patients who are alive at the end of the study and have no progression will be censored with the last available date. For review of the primary endpoint a central expert panel will be implemented.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
defined as time from randomisation to first observation of disease progression, censoring for death or drop out without progression |
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E.5.2 | Secondary end point(s) |
Overall survival, Progression free survival, Best response rate according to IMWG criteria, Safety parameters, Change in Karnofsky Index from baseline to EoT, Quality of life assessed by EQ-5D, Rate of sceletal related events, Rate of necessity for dialysis due to renal insufficiency |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
study end, End of Treatmenmt |
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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 | 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) | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
combination of bortezomib and dexamethasone with or without cyclophosphamide |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 32 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
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Last visit of last subject |
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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 | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |