A Trial for Systemic Light-chain (AL) Amyloidosis (EMN-03)

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2011 by European Myeloma Network
Sponsor:
Information provided by (Responsible Party):
European Myeloma Network
ClinicalTrials.gov Identifier:
NCT01277016
First received: January 10, 2011
Last updated: September 16, 2013
Last verified: January 2011
  Purpose

In this multi-center phase III trial, untreated patients diagnosed with AL who are not candidates for stem cell transplant with melphalan 200 mg/m2 are the target population. Stage I and II patients will be eligible. Stage III patients will be enrolled in an ancillary phase II study. Eligible patients will be stratified as cardiac stage I or stage II and then randomized to receive MDex or BMDex.

Primary objective is to compare hematologic(clonal) response i.e. the rate of complete response (CR) + partial response (PR) defined according to the criteria of the International Society for Amyloidosis consensus.


Condition Intervention Phase
AL Amyloidosis
Drug: BMDex
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Open-label Multicenter Phase III Trial of Melphalan and Dexamethasone (MDex) Versus Bortezomib, Melphalan and Dexamethasone (BMDex) for Untreated Patients With Systemic Light-chain (AL) Amyloidosis

Resource links provided by NLM:


Further study details as provided by European Myeloma Network:

Primary Outcome Measures:
  • Number of Patients in CR and PR measured by level of serum light chain monoclonal protein [ Time Frame: 3 cycles of therapy ] [ Designated as safety issue: No ]

    As defined by the International Society for Amyloidosis consensus.

    Complete response:

    • serum and urine IF negative,
    • normal FLC ratio,
    • bone marrow PC <5%

    Partial response if:

    • serum monoclonal >0.5 g/dL, a 50% reduction,
    • FLC in urine visible and >100 mg/day and 50% reduction,
    • FLC >2 times upper normal and 50% reduction.

    Progressive disease

    • from CR, abnormal FLC ratio
    • from PR or stable disease, 50% increase in monoclonal protein to >0.5 g/dL, or 50% increase in urine to >200 mg/day, or FLC increase of 50% to >100 mg/L.

    Stable disease: no CR, no PR, no progression.



Secondary Outcome Measures:
  • Compare haematology response [ Time Frame: 2 years ] [ Designated as safety issue: No ]

    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.


Estimated Enrollment: 110
Study Start Date: January 2011
Estimated Study Completion Date: June 2016
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: MDex:

MDex:

Administration of oral melphalan (M) at 0.22 mg/kg and dexamethasone (Dex) at 40 mg daily for 4 consecutive days every 28 days (MDex) until end of therapy

Experimental: BMDex

BMDex:

cycles 1 and 2 = MDex with bortezomib (B) at 1.3 mg/m2 i.v. on days 1, 4, 8 and 11 of a 28 day cycle, cycles 3 - 8 = MDex with bortezomib at 1.3 mg/m2 i.v. on days 1, 8, 15 and 22 of a 35 day cycle.

Drug: BMDex

BMDex:

cycles 1 and 2 = MDex with bortezomib (B) at 1.3 mg/m2 i.v. on days 1, 4, 8 and 11 of a 28 day cycle, cycles 3 - 8 = MDex with bortezomib at 1.3 mg/m2 i.v. on days 1, 8, 15 and 22 of a 35 day cycle.

Other Names:
  • Bortezomid
  • Melphalan
  • Dexametasone

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 of kappa or 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; al least one of the following criteria:
  • monoclonal protein >10 g/L in serum,
  • amyloid-forming (involved) FLC >75 mg/L with an abnormal K/L ratio,
  • difference between involved and uninvolved FLC >50 mg/L,
  • bone marrow with a clonal predominance.
  • Symptomatic organ involvement (heart, kidney, liver/GI tract, peripheral nervous system). Definition of organ involvement is defined.
  • Hemoglobin ≥11 g/dL, absolute neutrophil count ≥1500/mikroL, platelets ≥140,000/mikroL.
  • 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.

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. These subject can be enrolled in the ancillary phase II study.
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01277016

Contacts
Contact: Giampaolo Merlini, Proff 0382-502994 gmerlini@unipv.it
Contact: Giovanni Palladini, Proff 0382-502994 g.palladini@smatteo.pv.it

Locations
Italy
Amyloidosis Research and Treatment Center Recruiting
Pavia, Italy
Contact: Giovanni Palladini, Proff    0382-502994    g.palladini@smatteo.pv.it   
Principal Investigator: Giampaolo Merlini, Proff         
Sponsors and Collaborators
European Myeloma Network
  More Information

Additional Information:
Publications:
Responsible Party: European Myeloma Network
ClinicalTrials.gov Identifier: NCT01277016     History of Changes
Other Study ID Numbers: EMN-03, 2010-022395-31
Study First Received: January 10, 2011
Last Updated: September 16, 2013
Health Authority: Italy: National Bioethics Committee
Denmark: The Danish National Committee on Biomedical Research Ethics
United Kingdom: Research Ethics Committee
Netherlands: Medical Ethics Review Committee (METC)
Germany: Ethics Commission
France: National Consultative Ethics Committee for Health and Life Sciences
Spain: Comité Ético de Investigación Clínica
Greece: Ethics Committee
Norway: Ethics Committee
Sweden: Regional Ethical Review Board

Keywords provided by European Myeloma Network:
Amyloidosis
Bortezomib

Additional relevant MeSH terms:
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases
Dexamethasone
Bortezomib
Melphalan
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors

ClinicalTrials.gov processed this record on September 30, 2014