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Melphalan and Dexamethasone With or Without Bortezomib in Treating Patients With Previously Untreated Systemic Light-Chain Amyloidosis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01078454
First received: February 27, 2010
Last updated: November 20, 2014
Last verified: April 2014
  Purpose

This randomized phase III trial is studying melphalan and dexamethasone to see how well they work with or without bortezomib in treating patients with previously untreated systemic amyloidosis. Drugs used in chemotherapy, such as melphalan and dexamethasone, work in different ways to stop the growth of plasma cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of plasma cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving melphalan together with dexamethasone is more effective with or without bortezomib in treating systemic amyloidosis.


Condition Intervention Phase
Light Chain Deposition Disease
Primary Systemic Amyloidosis
Drug: melphalan
Drug: dexamethasone
Drug: bortezomib
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 Phase III Trial of Melphalan and Dexamethasone (MDex) Versus Bortezomib, Melphalan and Dexamethasone (BMDex) for Untreated Patients With Systemic Light-Chain (AL) Amyloidosis Ineligible for Autologous Stem-Cell Transplantation

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Proportion of Patients With Hematologic Overall Response (Partial Response [PR]+ Very Good PR [VGPR]+ Amyloid Complete Response [ACR]+ Stringent Complete Response [sCR]) After 3 Months (3 Cycles) of Therapy [ Time Frame: Assessed at 3 months ] [ Designated as safety issue: No ]
    sCR: ACR and no clonal cells in bone marrow (BM) ACR: Negative serum/urine immunofixation (IF), <5% plasma cells in BM, and normal serum FLC ratio VGPR: 1. PR and any of the following; 2. serum/urine M-protein detectable by IF but not measurable (NM) on electrophoresis (EP); (3) ≥90% reduction in serum M-component and urine M-protein <100 mg/24 hr if baseline serum measurable; (4) urine M-component <100 mg/24 hr and NM serum M-protein on serum protein EP if baseline urine measurable; (5) ≥90% drop in the difference between involved and uninvolved FLC levels if only FLC measurable PR: (1) ≥50% drop of serum M-protein and 24-hr urinary M-protein drop by ≥90% or to <200 mg/24 hr if baseline serum/urine measurable; or (2) ≥50% drop of serum M-protein if only serum measurable at baseline; or (3) 24-hr urinary M-protein drop by ≥90% or to <200 mg/24 hr if baseline urine measurable; or (4) ≥ 50% drop in the difference between involved and uninvolved FLC if only FLC measu


Enrollment: 11
Study Start Date: November 2010
Study Completion Date: February 2014
Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: ARM A (Mel-Dex)
Patients receive melphalan 0.22 mg/kg orally (PO) and dexamethasone 40 mg PO on days 1-4 every 4 weeks. Treatment repeats every 4 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity.
Drug: melphalan
Given PO
Other Names:
  • L-PAM
  • L-phenylalanine mustard
  • L-sarcolysin
  • Alkeran
  • NSC #8806
Drug: dexamethasone
Given PO
Other Names:
  • Decadron
  • Hexadrol
  • Dexameth
  • Dexone
  • DXM
Experimental: ARM B (B-Mel-Dex)
Patients receive melphalan 0.22 mg/kg PO and dexamethasone 40 mg PO on days 1-4 and bortezomib 1.3 mg/m^2 intravenously (IV) on days 1, 4, 8, and 11 every 4 weeks. Treatment repeats every 4 weeks for 2 cycles. Patients then receive melphalan PO and dexamethasone PO on days 1-4 and bortezomib IV on days 1, 8, 15, and 22 every 5 weeks. Treatment repeats every 5 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Drug: melphalan
Given PO
Other Names:
  • L-PAM
  • L-phenylalanine mustard
  • L-sarcolysin
  • Alkeran
  • NSC #8806
Drug: dexamethasone
Given PO
Other Names:
  • Decadron
  • Hexadrol
  • Dexameth
  • Dexone
  • DXM
Drug: bortezomib
Given IV
Other Names:
  • Velcade®
  • PS-341
  • MLN-341
  • LDP-341

  Show Detailed Description

  Eligibility

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

Inclusion Criteria:

  • Histologically confirmed diagnosis of systemic light-chain amyloidosis

    • Histologic diagnosis of disease must be confirmed by pathology (positive Congo red stain with green birefringence on polarized light microscopy)
    • Genetic testing must be negative for transthyretin mutations associated with hereditary amyloidosis (required in patients who are African-American or who present with peripheral neuropathy as the dominant organ involvement)
  • Measurable disease, defined by >= 1 of the following:

    • Serum M-protein >= 1 g/dL by serum protein electrophoresis (SPEP)
    • Difference between involved and uninvolved free light chain be >4.0mg/dL provided the kappa to lambda free light chain (FLC) ratio is abnormal
  • Symptomatic organ involvement* (heart, kidney, liver/gastrointestinal tract, peripheral nervous system, or soft tissue), defined as any of the following:

    • NOTE: *Carpal tunnel syndrome skin purpura or the presence of vascular amyloid on a bone marrow biopsy alone are not sufficient to meet criteria for "symptomatic organ involvement"
    • Renal involvement is defined as proteinuria (predominantly albumin) > 0.5 g/day by 24-hour urine collection
    • Cardiac involvement is defined as the presence of a mean left ventricular wall thickness of > 12 mm by echocardiogram in the absence of a history of hypertension or valvular heart disease or in the presence of unexplained low voltage (< 0.5 mV) by electrocardiogram
    • Hepatic involvement is defined as hepatomegaly or an alkaline phosphatase > 1.5 times upper limit of normal (ULN)
    • Peripheral nerve involvement is defined by clinical history or abnormal sensory and/or motor findings on neurologic exam
    • Gastrointestinal (GI) involvement is defined as gross GI bleeding or diarrhea (at least 4 stools per day over baseline); a positive GI biopsy is not sufficient to document clinical involvement
    • Autonomic nerve involvement is defined as orthostasis, symptoms of nausea or dysgeusia, gastric atony by gastric emptying scan, diarrhea, or constipation
    • Soft tissue and lymphatic involvement may be ascertained based on classic physical exam findings (macroglossia, shoulder pad sign, raccoon eyes, carpal tunnel syndrome, synovial enlargement, firm enlarged lymph nodes) or biopsy
  • Ineligible for autologous stem cell transplantation with melphalan 200 mg/m^2 or refuses to undergo transplantation
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Amyloid cardiac biomarker stage I or II disease

    • The amyloid cardiac staging system is based on NT-proBNP and troponin-T levels. If troponin T (cTnT) is not available at local institution then troponin I (cTnI) may be used. Thresholds for cTnT, cTnI, and NT-proBNP are < 0.035 ug/L, < 0.1 ug/L, and < 332 ng/L, respectively. Stage I patients have both troponin-T (or I) and NT-proBNP below the threshold. Stage II patients have either troponin-T (I) or NT-proBNP above the threshold. Stage III patients have troponin-T (or I) and simultaneous NT-proBNP above the threshold. Stage III patients are further classified as "better risk" if NT-proBNP is over 332 ng/L but less than 6000 ng/L
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • The absence of supine systolic blood pressure < 100 mmHg and difficult to manage symptomatic orthostatic hypotension
  • Absolute neutrophil count (ANC) > 1,500/mm^3
  • Platelet count > 140,000/mm^3
  • Hemoglobin > 10 g/dL
  • Total bilirubin < 2.5 mg/dL
  • Alkaline phosphatase < 5 times upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) < 3 times ULN
  • Creatinine clearance > 30 mL/min
  • Bone marrow plasma cells < 30%
  • Human immunodeficiency virus (HIV)-positivity allowed provided the following criteria are met:

    • No history of acquired immunodeficiency syndrome (AIDS)-defining events including history of CD4 cell count < 200/mm^3
    • Current CD4 cell count >= 350/mm^3
    • Not receiving zidovudine or stavudine
    • No secondary amyloidosis
  • More than 3 weeks since radiotherapy

    • Enrollment of subjects who require radiotherapy (which must be localized in field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy
  • More than 14 days since prior and no concurrent participation in clinical trials with other investigational agents not included in this trial

Exclusion Criteria:

  • Pregnant or nursing
  • Clinically overt myeloma (hypercalcemia or lytic bone lesions)
  • Prior chemotherapy or radiotherapy for the treatment of myeloma or systemic light-chain amyloidosis
  • History of sustained ventricular tachycardias
  • Cardiac syncope
  • Uncompensated New York Heart Association (NYHA) class III or IV congestive heart failure
  • Uncontrolled infection
  • Active malignancy within the past 5 years except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or adequately treated stage I cancer currently in complete remission
  • Serious medical or psychiatric illness likely to interfere with study participation, including recent myocardial infarction (within the past 6 months) or poorly controlled diabetes mellitus
  • Hypersensitivity to bortezomib, boron, or mannitol
  • Grade 2 or higher peripheral neuropathy
  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: NCT01078454

  Show 209 Study Locations
Sponsors and Collaborators
Investigators
Study Chair: Angela Dispenzieri, M.D. Mayo Clinic
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01078454     History of Changes
Other Study ID Numbers: NCI-2011-02010, NCI-2011-02010, E4A08, U10CA021115
Study First Received: February 27, 2010
Results First Received: November 20, 2014
Last Updated: November 20, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):
Melphalan
Dexamethasone
Bortezomib
Systemic Light-chain (AL) Amyloidosis

Additional relevant MeSH terms:
Amyloidosis
Metabolic Diseases
Proteostasis Deficiencies
BB 1101
Bortezomib
Dexamethasone
Dexamethasone 21-phosphate
Dexamethasone acetate
Melphalan
Alkylating Agents
Anti-Inflammatory Agents
Antiemetics
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antineoplastic Agents, Hormonal
Autonomic Agents
Central Nervous System Agents
Enzyme Inhibitors
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Protease Inhibitors

ClinicalTrials.gov processed this record on November 25, 2014