E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 10002022 |
E.1.2 | Term | Amyloidosis |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
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 |
To compare hematologic response after 3 cycles in patients treated with MDex or BMDex |
|
E.2.2 | Secondary objectives of the trial |
To compare in patients treated with MDex or BMDex:
- complete hematologic response rate after 3 cycles and after completion of therapy;
- hematologic response rate at completion of therapy;
- organ response rates at 3, 6, 9 and 12 months;
- treatment-related mortality;
- toxicity;
- overall and progression-free survival;
- time to hematologic and organ response;
- quality of life.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Histologic diagnosis of amyloidosis.
- Genetic testing must be negative for transthyretin mutations associated with hereditary amyloidosis or immunohistochemistry of amyloid deposits must provide clear evidence kappa and lambda light chains in those who present with peripheral neuropathy or heart as the dominant organ involvement.
- Not eligible for ASCT with melphalan 200 mg/m2 . Patients who are eligible for SCT with melphalan 200 mg/m2 but decline the procedure, can be enrolled in the study, but are stratified in a separate stratum before randomization.
- Patients must be >/= 18 years of age.
- ECOG performance status 0,1 or 2.
- Measurable disease; at least one of the following criteria:
a) monoclonal protein >10 g/L in serum,
b) amyloid-forming (involved) FLC >75 mg/L with an abnormal Kappa/lampda- ratio,
c) difference between involved and uninvolved FLC >50 mg/L,
d) bone marrow with a clonal predominance.
- Symptomatic organ involvement (heart, kidney, liver/GI tract, peripheral nervous system).
- Hemoglobin ≥11 g/dL, absolute neutrophil count ≥1500/microL, platelets ≥140,000/microL.
-Total bilirubin <2.5 mg/dL, alkaline phosphatase <5 × u.l.n., ALT <3 × u.l.n..
- Estimated glomerular filtration rate (eGFR) by the MDRD formula >30 ml/min.
- Only patients who are informed of the investigational nature of this study and sign and give written informed consent in accordance with institutional, national and European guidelines are eligible to participate.
-Women must be either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e. a hormonal contraceptive, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. All
females of childbearing potential must have a blood test or urine study within 2 weeks
prior to registration to rule out pregnancy.
- Men must agree to use an acceptable method for contraception for the duration of the study. |
|
E.4 | Principal exclusion criteria |
- Amyloid-specific syndrome, such as carpal tunnel syndrome or skin purpura as the only evidence of disease. The finding of isolated vascular amyloid in a bone marrow biopsy
specimen or in a plasmacytoma is not indicative of systemic amyloidosis.
- Isolated soft tissue involvement.
- Presence of non-AL amyloidosis.
- Previous treatment for plasma cell disease. A single previous cycle of dexamethasone or steroid equivalent (maximum cumulative dexamethasone dose 160 mg) is allowed; in this case baseline data must be obtained after steroid administration. Previous stem cell harvest is allowed, provided that mobilization is performed with G-CSF only.
- Bone marrow plasma cells >30%.
- Cardiac stage III disease: both cTnT > 0.035 ng/mL (or in place of cTnT the cTnI > 0.10 ng/mL) AND simultaneous NT-proBNP >332 ng/L.
- Repetitive ventricular arrhythmias on 24h Holter ECG in spite of anti-arrhythmic treatment.
- Chronic atrial fibrillation
- Supine systolic blood pressure <100 mmHg or symptomatic orthostatic hypotension or clinically important autonomic disease
- Grade 3 sensory or grade 1 painful peripheral neuropathy.
- Patients with AL who are eligible for ASCT with 200 mg/m2 of melphalan. These are patients </= 65 years of age, without cardiac involvement (determined according to the consensus criteria), with eGFR >51mL/min, left ventricular ejection fraction >45%, and bilirubin </=2.0 mg/dL. Patients who are eligible for SCT with melphalan 200 mg/m2 but decline the procedure, can be enrolled in the study, but are stratified in a separate stratum before randomization.
- Pregnant or nursing women.
- Clinically overt multiple myeloma with lytic bone lesions
- Patients with uncontrolled infection or active malignancy with the exception of adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years.
- Patients with medically documented cardiac syncope, uncompensated NYHA Class 3 or 4 congestive heart failure, or myocardial infarction within the previous 6 months are not eligible.
- HIV positive.
- Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study.
- Patients with hypersensitivity to bortezomib, boron or mannitol. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Hematologic response after 3 cycles of therapy |
|
E.5.2 | Secondary end point(s) |
1. complete hematologic response rate
2. hematologic response rate
3. organ response rates
4. treatment related mortality
5. toxicity
6. overall and progression-free survival
7. time to hematologic and organ response
8. quality of life |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. after 3 cycles and after completion of therapy
2. at completion of therapy
3. at 3, 6, 9, 12 months
8. before each cycle, at End of treatment visit, Every 6 weeks before progression, Every 3 months after progression |
|
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 |
|
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
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 | No |
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 |
Denmark |
France |
Germany |
Greece |
Italy |
Netherlands |
Spain |
Sweden |
United Kingdom |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |