E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Multiple myeloma (MM) is a malignant, lymphoproliferative disease of the B-cell system. The incidence is approximately 4 per 100,000 and it is age-dependent, with an increase in incidence of approximately 6 8 per 100,000 between the ages of 70 and 80 years. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8_0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028228 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to compare the time to progression (TTP) of three daily doses of thalidomide (100, 200 and 400 mg) with high-dose dexamethasone in relapsed refractory multiple myeloma (MM) patients and to subsequently select the optimum thalidomide dose in terms of median TTP and toxicity. |
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E.2.2 | Secondary objectives of the trial |
The important secondary objectives are to compare each dose of thalidomide with high-dose dexamethasone for the following outcomes: · response rate; · clinical benefit; · survival (overall and progression free); · quality of life. · TTP in the subgroups defined by the number of therapeutic lines before randomisation (1 line versus more than 1 line).
The safety of thalidomide compared to dexamethasone will also be evaluated.
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria to be eligible for enrolment and randomisation into the study: · Male or female patients, aged ≥ 18 years at the time of signing the informed consent form; · Patients who have been previously diagnosed with MM (see Appendix 3 for the standard definition of MM), who have received between 1 and 3 prior lines of treatment for their disease (see Appendix 4 for definition of line of treatment), and who require therapy because of disease progression (see Appendix 1 for PD definition); · Secretory MM with measurable levels of monoclonal protein in serum (> 10 g/L of IgG M protein or > 5 g/L of IgA M-protein) or urine (≥ 200 mg/24hours); Patient with the following rare subclasses of the immunoglobulin: IgD, IgE, IgM can be included in the study if the level of monoclonal protein in serum is > 5 g/L or ≥ 200 mg/24hours in urine. As IgM immunoglobulin isotype can be related to Waldenstrom's macroglobulinemia, it ia important to distinguish and not include in the study patients with Waldenstrom's macroglobulinemia. · ECOG performance status of 0, 1, or 2 (see Appendix 5); · Life expectancy > 3 months; · Able to adhere to the study visit schedule and other protocol requirements; · Women of child-bearing 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 the therapy, during the Treatment Period, and for 4 weeks after the last dose; · Males must agree to use barrier contraception (latex condoms) when engaging in reproductive activity during the Treatment Period and for 4 weeks after the last dose; · Written, informed consent.
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E.4 | Principal exclusion criteria |
The presence of any of the following will exclude a patient from study enrolment: · Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the Informed Consent Form (ICF); · Pregnant or lactating women. A serum β-hCG pregnancy test must be performed at the Screening visit, for female patients of child-bearing potential. If the test is positive, the patient must be excluded from the study. Confirmation that the patient is not pregnant must be established by a negative serum or urinary pregnancy test with the result obtained 1 day prior to the Baseline visit (or the day of the visit if results are available before drug delivery). A pregnancy test is not required for naturally post-menopausal women (who have not had menses at any time in the preceding 24 consecutive months) or surgically sterilised women (hysterectomy, bilateral ovariectomy, bilateral salpingectomy); · Non-secretory MM; · Any of the following laboratory abnormalities: - Absolute neutrophil count (ANC) < 500 cells/mm3 (0.5 x 109/L); - Platelet count < 30,000/mm3 (30.0 x 109/L) without transfusion support within 7 days before the test; - Serum creatinine > 3.0 mg/dL (265 µmol/L); - Serum aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) > 3.0 x upper limit of normal (ULN); - Serum total bilirubin > 2.0 mg/dL (34 µmol/L); · Any condition, including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study, or which confounds the ability to interpret data from the study; · Severe cardiac dysfunction (according to the New York Heart Association [NYHA] classification III-IV [see Appendix 6]); · Severe bradycardia (< 50 bpm); · Peripheral neuropathy ≥ Grade 2 in severity (according to the NCI CTC Version 3.0 – see Appendix 7); · Prior history of malignancy (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless the patient has been free of disease for ≥ 5 years; · Patient received any chemotherapy, corticosteroids (> 10 mg/day prednisone or equivalent as a continuous dose) within 4 weeks before randomisation; · Previously treated with thalidomide or thalidomide derivatives; · Patients refractory to high-dose dexamethasone (defined as experiencing less than a PR to dexamethasone, or PD within 6 months after discontinuing dexamethasone, or discontinued dexamethasone because of ≥ Grade 3 dexamethasone-related toxicity. Previous high-dose dexamethasone therapy is defined as > 500 mg dexamethasone or equivalent over a 10-week period, whether administered alone or as part of the VAD regimen); · Contraindications for high-dose dexamethasone; · Active or chronic gastrointestinal ulcers, active viral infections (herpes, varicella, HIV, hepatitis B, hepatitis C), glaucoma, uncontrolled hypertension, or diabetes mellitus, unless well controlled and under strict supervision during dexamethasone treatment; · Patient enrolled in another clinical trial or who have participated in another trial within the last 4 weeks before randomisation.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint in this study is the evaluation of IRC-documented time to progression (TTP). The TTP is calculated as the time from randomisation to the first documentation of PD, based on the myeloma response determination EBMT criteria (see Appendix 1). When disease progression is based on increasing monoclonal protein levels it must be confirmed at least once within 1 to 4 weeks after the first determination of disease progression. Thus if the second monoclonal protein measurement confirms disease progression, TTP will be calculated from randomisation to the time of the first monoclonal protein measurement. Disease progression based on bone marrow findings, worsening lytic bone disease, progressively enlarging, extramedullary plasmacytomas, or hypercalcaemia does not require a second confirmatory measurement.
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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 | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | No |
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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The last visit of the last subject undergoing the clinical trial. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 10 |