A Trial for Systemic Light-chain (AL) Amyloidosis

NCT01277016 | Completed Phase 3 DMC

• 2 other identifiers: EMN-032010-022395-31
• Study Type: interventional
• Target: 110
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

AL Amyloidosis

Keywords

Amyloidosis; Bortezomib

Outcome Measures

Primary Outcomes (1)

• Number of Patients in CR and PR measured by level of serum light chain monoclonal protein

  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.

  3 cycles of therapy

Secondary Outcomes (1)

• Compare haematology response

  2 years

Study Arms (2)

MDex:

NO INTERVENTION

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

BMDex

EXPERIMENTAL

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

Interventions

BMDex DRUG

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.

Also known as: Bortezomid, Melphalan, Dexametasone

BMDex

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• European Myeloma Network B.V.: lead

Study Sites (1)

Amyloidosis Research and Treatment Center

Pavia, Italy

Location

Related Publications (2)

• Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. doi: 10.1200/JCO.2009.23.8220. Epub 2010 Jan 19.

  PMID: 20085941 RESULT

• Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hajek R, Moreau P, Jaccard A, Schonland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. doi: 10.1200/JCO.20.01285. Epub 2020 Jul 30.

  PMID: 32730181 DERIVED

Related Links

• "Click here for more information about this study:" EMN-03

MeSH Terms

Conditions

Immunoglobulin Light-chain Amyloidosis; Amyloidosis

Interventions

Melphalan

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Paraproteinemias

Intervention Hierarchy (Ancestors)

Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Giovanni mr Palladini, Proff

  Amyloidosis Research and Treatment Center, Pavia, Italy

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 10, 2011
• First Posted: January 14, 2011
• Study Start: January 1, 2011
• Primary Completion: February 1, 2016
• Study Completion: July 31, 2016
• Last Updated: March 10, 2017

Record last verified: 2016-08

Locations

IT (1)