Bortezomib, Melphalan, and Dexamethasone in Treating Patients With Primary Amyloidosis or Light Chain Deposition Disease

Sponsor
Barbara Ann Karmanos Cancer Institute (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT00520767
Collaborator
National Cancer Institute (NCI) (NIH)
35
Enrollment
7
Locations
1
Arm
171
Duration (Months)
5
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Giving bortezomib together with melphalan and dexamethasone may be an effective treatment for primary amyloidosis and light chain deposition disease.

PURPOSE: This phase II trial is studying how well giving bortezomib together with melphalan and dexamethasone works in treating patients with primary amyloidosis or light chain deposition disease.

Condition or DiseaseIntervention/TreatmentPhase
Phase 2

Detailed Description

OBJECTIVES:

Primary

  • Determine the complete hematologic response rate at 12 months.

Secondary

  • Determine the overall hematologic response rate.

  • Determine the organ response rate.

  • Determine time to treatment failure.

  • Assess toxicity of the regimen, in terms of incidence and severity of treatment-emergent peripheral neuropathy and quality of life.

  • Determine the overall survival.

OUTLINE: This is a multicenter study.

Patients receive oral melphalan on days 1-4, bortezomib IV on days 1, 8, 15, and 22, and dexamethasone orally or IV on days 1, 2, 8, 9, 15, 16, 22, and 23. Treatment repeats every 4-6 weeks for up to 20 courses in the absence of disease progression or unacceptable toxicity.

Blood, urine, and bone marrow aspirates are collected at baseline and periodically after treatment to permit the correlation of clinical results with measured molecular events. A single baseline peripheral blood DNA sample is collected for future association studies linking disease onset, progression, and response to administered therapy with single nucleotide polymorphisms. Blood plasma and urine samples are evaluated for proteomic markers associated with disease progression and therapeutic response. Peripheral blood RNA samples are evaluated for transcriptional response to treatment of peripheral blood lymphocytes. Bone marrow aspirates are collected to extract plasma cells by flow cytometry for gene expression profiling.

Quality of life is assessed at the beginning of each course.

Study Design

Study Type:
Interventional
Actual Enrollment :
35 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Multicenter Phase II Trial of Bortezomib (Velcade), Melphalan, and Dexamethasone (V-MD) in Patients With Symptomatic AL-Amyloidosis or Light Chain Deposition Disease
Study Start Date :
Sep 1, 2007
Actual Primary Completion Date :
Oct 1, 2010
Anticipated Study Completion Date :
Dec 1, 2021

Arms and Interventions

ArmIntervention/Treatment
Experimental: Melphalan, Dexamethasone, Bortezomib,

Bortezomib 1.3 mg/m2 days 1, 8, 15, 22; Dexamethasone 40 mg/d days 1, 2, 8, 9, 15, 16, 22, 23; Melphalan 9 mg/m2/day days 1-4

Drug: bortezomib
Bortezomib 1.3 mg/m2 days 1, 8, 15, 22
Other Names:
  • Velcade
  • Drug: dexamethasone
    Dexamethasone 40 mg/d days 1, 2, 8, 9, 15, 16, 22, 23
    Other Names:
  • Dexasone
  • Decadron
  • Diodex
  • Hexadrol
  • Maxidex
  • Dexamethasone Sodium Phosphate
  • Dexamethasone Acetate
  • Drug: melphalan
    Melphalan 9 mg/m2/day days 1-4
    Other Names:
  • Alkeran®
  • L-PAM
  • L-Sarcolysin
  • Phenylalanine Mustard
  • Genetic: microarray analysis
    ≤28 days prior to enrollment

    Other: flow cytometry
    Day 1 of cycles 6, 12, 18 and at end of study.

    Other: laboratory biomarker analysis
    ≤28 days prior to enrollment

    Procedure: quality-of-life assessment
    Start of each cycle

    Outcome Measures

    Primary Outcome Measures

    1. Complete Hematologic Response [Up to 12 months]

    Secondary Outcome Measures

    1. Overall Survival [Day 1 of Each Cycle and every 12 weeks after last treatment cycle]

    2. Time to Treatment Failure [Day 1 of Each Cycle]

    3. Change in Quality of Life From Baseline as Assessed by the Functional Assessment of Cancer Therapy-Neurotoxicity Questionnaire. [At the start of each cycle]

    4. Organ Response Rate (OrR) [Beginning of cycles 4, 8, 12, 16 and 20, at follow up and end of study.]

    5. Toxicity, Including Neurotoxicity [Day 1 of Each Cycle]

    6. Overall Hematologic Response Rate (OHR) [Beginning of cycles 4, 8, 12, 16 and 20, at follow up and end of study.]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 120 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    DISEASE CHARACTERISTICS:
    • Biopsy-proven diagnosis of 1 of the following:

    • Primary systemic amyloidosis

    • Histochemical diagnosis of amyloidosis determined by polarizing microscopy of green bi-refringent material in Congo red-stained tissue specimens or characteristic electron microscopy appearance

    • Light chain deposition disease

    • Measurable disease as defined by one or more of the following:

    • Serum monoclonal protein ≥ 0.5 g/dL by serum electrophoresis

    • Urine monoclonal protein > 200 mg/tv in a 24 hr urine electrophoresis

    • Serum immunoglobulin free-light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin kappa lambda free light chain ratio

    • Must meet 1 of the following criteria:

    • Clonal population of plasma cells in the bone marrow (≤ 30%)

    • Immunohistochemical stain with anti-light chain anti-sera of amyloid fibrils

    • Must not meet the following diagnostic criteria for symptomatic* multiple myeloma:

    • Lytic lesions on skeletal survey

    • Plasmacytoma

    • Increase in bone marrow plasma cells ≥ 30% NOTE: *Patients who meet the International Myeloma Working Group definition of symptomatic multiple myeloma with symptoms attributable only to associated amyloidosis and who do not otherwise meet the criteria for diagnosis of smoldering myeloma are potentially eligible upon approval of the principal investigator.

    • If not previously treated, patient is either not a candidate for autologous stem cell transplantation (ASCT) or has declined the option of ASCT

    • Patients who have undergone prior ASCT and have subsequently progressed are eligible, provided other eligibility criteria are met

    • No secondary or familial amyloidosis

    PATIENT CHARACTERISTICS:
    • ECOG performance status 0-3

    • Creatinine < 5 mg/dL

    • Bilirubin < 2.5 times upper limit of normal (ULN)

    • ALT and AST < 3 times ULN

    • Absolute neutrophil count ≥ 1,000/mm³

    • Platelet count ≥ 80,000/mm³

    • Not pregnant or nursing

    • Negative pregnancy test

    • Fertile patients must use effective contraception

    • Peripheral sensory neuropathy < grade 3

    • No myocardial infarction within the past 6 months

    • No New York Heart Association class III or IV heart failure

    • No uncontrolled angina

    • No severe uncontrolled ventricular arrhythmias

    • No EKG* evidence of acute ischemia or active conduction system abnormalities (not including 1st degree AV-block, Wenckebach type 2nd degree heart block, or left bundle branch block) NOTE: *Prior to study entry, any EKG screening abnormality must be documented by the investigator as not medically relevant; there is no lower limit of LVEF below which patients are excluded from participation

    • No hypersensitivity to bortezomib, boron, or any of the other agents utilized in this study

    • No serious concurrent illness (e.g., stroke) within the past 30 days

    • No psychiatric illness likely to interfere with study participation

    • No untreated HIV infection

    • Patients with asymptomatic HIV infection on active antiretroviral therapy are potentially eligible

    • No diagnosis or treatment of another malignancy within the past 3 years, except completely resected basal cell or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy

    PRIOR CONCURRENT THERAPY:
    • See Disease Characteristics

    • No other investigational drugs within the past 14 days

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Rocky Mountain Cancer Centers/Rocky Mountain Blood & Marrow Transplant ProgramDenverColoradoUnited States80218
    2Boston University Cancer Research CenterBostonMassachusettsUnited States02118
    3Barbara Ann Karmanos Cancer InstituteDetroitMichiganUnited States48201-1379
    4Josephine Ford Cancer Center at Henry Ford HospitalDetroitMichiganUnited States48202
    5Providence Cancer Institute at Providence Hospital - Southfield CampusSouthfieldMichiganUnited States48075
    6Duke Comprehensive Cancer CenterDurhamNorth CarolinaUnited States27710
    7UPMC Cancer CentersPittsburghPennsylvaniaUnited States15232

    Sponsors and Collaborators

    • Barbara Ann Karmanos Cancer Institute
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Jeffrey A. Zonder, MD, Barbara Ann Karmanos Cancer Institute

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Jeffrey Zonder, Principal Investigator, Barbara Ann Karmanos Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT00520767
    Other Study ID Numbers:
    • CDR0000555016
    • P30CA022453
    • WSU-2006-132
    • MILLENNIUM-WSU-2006-132
    • WSU-HIC-060907M1F
    First Posted:
    Aug 27, 2007
    Last Update Posted:
    Apr 6, 2021
    Last Verified:
    Mar 1, 2021

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleMelphalan, Dexamethasone, Bortezomib,
    Arm/Group DescriptionBortezomib 1.3 mg/m2 days 1, 8, 15, 22; Dexamethasone 40 mg/d days 1, 2, 8, 9, 15, 16, 22, 23; Melphalan 9 mg/m2/day days 1-4 bortezomib: Bortezomib 1.3 mg/m2 days 1, 8, 15, 22 dexamethasone: Dexamethasone 40 mg/d days 1, 2, 8, 9, 15, 16, 22, 23 melphalan: Melphalan 9 mg/m2/day days 1-4 microarray analysis: ≤28 days prior to enrollment flow cytometry: Day 1 of cycles 6, 12, 18 and at end of study. laboratory biomarker analysis: ≤28 days prior to enrollment quality-of-life assessment: Start of each cycle
    Period Title: Overall Study
    STARTED35
    COMPLETED33
    NOT COMPLETED2

    Baseline Characteristics

    Arm/Group TitleMelphalan, Dexamethasone, Bortezomib,
    Arm/Group DescriptionBortezomib 1.3 mg/m2 days 1, 8, 15, 22; Dexamethasone 40 mg/d days 1, 2, 8, 9, 15, 16, 22, 23; Melphalan 9 mg/m2/day days 1-4 bortezomib: Bortezomib 1.3 mg/m2 days 1, 8, 15, 22 dexamethasone: Dexamethasone 40 mg/d days 1, 2, 8, 9, 15, 16, 22, 23 melphalan: Melphalan 9 mg/m2/day days 1-4 microarray analysis: ≤28 days prior to enrollment flow cytometry: Day 1 of cycles 6, 12, 18 and at end of study. laboratory biomarker analysis: ≤28 days prior to enrollment quality-of-life assessment: Start of each cycle
    Overall Participants35
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    64
    Sex: Female, Male (Count of Participants)
    Female
    15
    42.9%
    Male
    20
    57.1%
    Region of Enrollment (participants) [Number]
    United States
    35
    100%

    Outcome Measures

    1. Primary Outcome
    TitleComplete Hematologic Response
    Description
    Time FrameUp to 12 months

    Outcome Measure Data

    Analysis Population Description
    Individuals evaluable for response
    Arm/Group TitleMelphalan, Dexamethasone, Bortezomib,
    Arm/Group DescriptionBortezomib 1.3 mg/m2 days 1, 8, 15, 22; Dexamethasone 40 mg/d days 1, 2, 8, 9, 15, 16, 22, 23; Melphalan 9 mg/m2/day days 1-4 bortezomib: Bortezomib 1.3 mg/m2 days 1, 8, 15, 22 dexamethasone: Dexamethasone 40 mg/d days 1, 2, 8, 9, 15, 16, 22, 23 melphalan: Melphalan 9 mg/m2/day days 1-4 microarray analysis: ≤28 days prior to enrollment flow cytometry: Day 1 of cycles 6, 12, 18 and at end of study. laboratory biomarker analysis: ≤28 days prior to enrollment quality-of-life assessment: Start of each cycle
    Measure Participants33
    Measure individuals33
    Number [participants]
    16
    45.7%
    2. Secondary Outcome
    TitleOverall Survival
    Description
    Time FrameDay 1 of Each Cycle and every 12 weeks after last treatment cycle

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    3. Secondary Outcome
    TitleTime to Treatment Failure
    Description
    Time FrameDay 1 of Each Cycle

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    4. Secondary Outcome
    TitleChange in Quality of Life From Baseline as Assessed by the Functional Assessment of Cancer Therapy-Neurotoxicity Questionnaire.
    Description
    Time FrameAt the start of each cycle

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    5. Secondary Outcome
    TitleOrgan Response Rate (OrR)
    Description
    Time FrameBeginning of cycles 4, 8, 12, 16 and 20, at follow up and end of study.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    6. Secondary Outcome
    TitleToxicity, Including Neurotoxicity
    Description
    Time FrameDay 1 of Each Cycle

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    7. Secondary Outcome
    TitleOverall Hematologic Response Rate (OHR)
    Description
    Time FrameBeginning of cycles 4, 8, 12, 16 and 20, at follow up and end of study.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group TitleMelphalan, Dexamethasone, Bortezomib,
    Arm/Group DescriptionBortezomib 1.3 mg/m2 days 1, 8, 15, 22; Dexamethasone 40 mg/d days 1, 2, 8, 9, 15, 16, 22, 23; Melphalan 9 mg/m2/day days 1-4 bortezomib: Bortezomib 1.3 mg/m2 days 1, 8, 15, 22 dexamethasone: Dexamethasone 40 mg/d days 1, 2, 8, 9, 15, 16, 22, 23 melphalan: Melphalan 9 mg/m2/day days 1-4 microarray analysis: ≤28 days prior to enrollment flow cytometry: Day 1 of cycles 6, 12, 18 and at end of study. laboratory biomarker analysis: ≤28 days prior to enrollment quality-of-life assessment: Start of each cycle
    All Cause Mortality
    Melphalan, Dexamethasone, Bortezomib,
    Affected / at Risk (%)# Events
    Total/ (NaN)
    Serious Adverse Events
    Melphalan, Dexamethasone, Bortezomib,
    Affected / at Risk (%)# Events
    Total12/35 (34.3%)
    Blood and lymphatic system disorders
    thrombocytopenia2/35 (5.7%) 2
    Edema2/35 (5.7%) 2
    Cardiac disorders
    Congestive Heart Failure1/35 (2.9%) 1
    Hypotension1/35 (2.9%) 1
    Ventricular Arrhythmia2/35 (5.7%) 2
    Hypertension2/35 (5.7%) 2
    cardiac Arrhythmia1/35 (2.9%) 1
    Gastrointestinal disorders
    Dehydration2/35 (5.7%) 2
    Nausea1/35 (2.9%) 1
    Vomiting1/35 (2.9%) 1
    General disorders
    Death2/35 (5.7%) 2
    Pain-chest wall1/35 (2.9%) 1
    Infections and infestations
    Infection with Normal ANC-Lung (pneumonia)2/35 (5.7%) 2
    Infection with Normal ANC-Catheter related1/35 (2.9%) 1
    Infection with Normal ANC-Skin (cellulitis)-shingles1/35 (2.9%) 1
    Metabolism and nutrition disorders
    Hyperglycemia1/35 (2.9%) 1
    Hyponatremia1/35 (2.9%) 1
    Creatinine2/35 (5.7%) 2
    Nervous system disorders
    syncope1/35 (2.9%) 1
    Pain-Headache2/35 (5.7%) 2
    Psychiatric disorders
    Mental Status Change2/35 (5.7%) 2
    Renal and urinary disorders
    Renal Failure1/35 (2.9%) 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnea2/35 (5.7%) 2
    Hypoxia2/35 (5.7%) 2
    Other (Not Including Serious) Adverse Events
    Melphalan, Dexamethasone, Bortezomib,
    Affected / at Risk (%)# Events
    Total3/35 (8.6%)
    Blood and lymphatic system disorders
    Hemoglobin2/35 (5.7%) 2
    Gastrointestinal disorders
    Constipation2/35 (5.7%) 2

    Limitations/Caveats

    Mix of previously treated & newly diagnosed pts (populations which may have different prognoses), plus the relatively small trial size limit conclusions one can draw re: relative efficacy of MDV (vs CyBorD or Mel-Dex, for example)

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleJeffrey Zonder, M.D.
    OrganizationBarbara Ann Karmanos Cancer Institute
    Phone313-576-8732
    Emailzonderj@karmanos.org
    Responsible Party:
    Jeffrey Zonder, Principal Investigator, Barbara Ann Karmanos Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT00520767
    Other Study ID Numbers:
    • CDR0000555016
    • P30CA022453
    • WSU-2006-132
    • MILLENNIUM-WSU-2006-132
    • WSU-HIC-060907M1F
    First Posted:
    Aug 27, 2007
    Last Update Posted:
    Apr 6, 2021
    Last Verified:
    Mar 1, 2021