Clinical trial NCT00520767: Bortezomib, Melphalan, and Dexamethasone in Treating Patients With Primary Amyloidosis or Light Chain Deposition Disease
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary Systemic Amyloidosis
Light Chain Deposition Disease
Keywords: primary systemic amyloidosis
light chain deposition disease
Lead sponsor: Barbara Ann Karmanos Cancer Institute
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-08-27
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.
* 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.

Eligibility criteria: 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

Primary outcomes:
measure: Complete Hematologic Response
timeFrame: Up to 12 months
Secondary outcomes:
measure: Overall Survival
timeFrame: time from day of registration until 72 months.
measure: Time to Treatment Failure (TTF)
timeFrame: start of treatment until 72 months
measure: Organ Response Rate (OrR)
timeFrame: Beginning of cycles 4, 8, 12, 16 and 20, at follow up and end of study.
measure: Overall Hematologic Response Rate (OHR)
timeFrame: Beginning of cycles 4, 8, 12, 16 and 20, at follow up and end of study.
Other outcomes:
Locations:
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers/Rocky Mountain Blood & Marrow Transplant Program
state: Colorado
city: Boston
country: United States
facility: Boston University Cancer Research Center
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Detroit
country: United States
facility: Josephine Ford Cancer Center at Henry Ford Hospital
state: Michigan
city: Southfield
country: United States
facility: Providence Cancer Institute at Providence Hospital - Southfield Campus
state: Michigan
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Pittsburgh
country: United States
facility: UPMC Cancer Centers
state: Pennsylvania
Study officials:
affiliation: Barbara Ann Karmanos Cancer Institute
name: Jeffrey A. Zonder, MD
role: PRINCIPAL_INVESTIGATOR
References: