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

Primary Systemic Amyloidosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00520767
• Other study ID #: 2006-132
• Secondary ID: P30CA022453MILLE
• Status: Completed
• Phase: Phase 2
• Start date: September 2007
• Est. completion date: June 6, 2019

Study information

• Verified date: December 2023
• Source: Barbara Ann Karmanos Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 35
• Est. completion date: June 6, 2019
• Est. primary completion date: October 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

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

Related Conditions & MeSH terms

• Amyloidosis
• Immunoglobulin Light-chain Amyloidosis
• Light Chain Deposition Disease
• Multiple Myeloma
• Primary Systemic Amyloidosis

Intervention

Drug:
• 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

Genetic:
• microarray analysis
=28 days prior to enrollment

Other:
• flow cytometry
Day 1 of cycles 6, 12, 18 and at end of study.
• laboratory biomarker analysis
=28 days prior to enrollment

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

Locations

Country	Name	City	State
United States	Boston University Cancer Research Center	Boston	Massachusetts
United States	Rocky Mountain Cancer Centers/Rocky Mountain Blood & Marrow Transplant Program	Denver	Colorado
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan
United States	Duke Comprehensive Cancer Center	Durham	North Carolina
United States	UPMC Cancer Centers	Pittsburgh	Pennsylvania
United States	Providence Cancer Institute at Providence Hospital - Southfield Campus	Southfield	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Barbara Ann Karmanos Cancer Institute	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Complete Hematologic Response		Up to 12 months
Secondary	Overall Survival	time from day of registration until day of death.	time from day of registration until 72 months.
Secondary	Time to Treatment Failure (TTF)	Time from start of treatment until date of documented disease progression, removal from protocol due to toxicity, or death from any cause.	start of treatment until 72 months
Secondary	Organ Response Rate (OrR)		Beginning of cycles 4, 8, 12, 16 and 20, at follow up and end of study.
Secondary	Overall Hematologic Response Rate (OHR)		Beginning of cycles 4, 8, 12, 16 and 20, at follow up and end of study.

External Links

•   Clinical trial summary from the National Cancer Institute's PDQ® database