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)
• Enrollment: 35
• Locations: 7
• Arm: 1
• Duration (Months): 176.7
• Patients Per Site: 5
• Patients Per Site Per Month: 0

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 Disease	Intervention/Treatment	Phase
Primary Systemic Amyloidosis; Light Chain Deposition Disease	Drug: bortezomib; Drug: dexamethasone; Drug: melphalan; Genetic: microarray analysis; Other: flow cytometry; Other: laboratory biomarker analysis; Procedure: quality-of-life assessment	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: May 23, 2022

Arms and Interventions

Arm

Intervention/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

	Site	City	State	Country	Postal Code
1	Rocky Mountain Cancer Centers/Rocky Mountain Blood & Marrow Transplant Program	Denver	Colorado	United States	80218
2	Boston University Cancer Research Center	Boston	Massachusetts	United States	02118
3	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201-1379
4	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan	United States	48202
5	Providence Cancer Institute at Providence Hospital - Southfield Campus	Southfield	Michigan	United States	48075
6	Duke Comprehensive Cancer Center	Durham	North Carolina	United States	27710
7	UPMC Cancer Centers	Pittsburgh	Pennsylvania	United States	15232

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:

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

Publications

None provided.

• Responsible Party: Jeffrey Zonder, Principal Investigator, Barbara Ann Karmanos Cancer Institute
• ClinicalTrials.gov Identifier: NCT00520767
• Other Study ID Numbers: 2006-132; P30CA022453; MILLENNIUM-WSU-2006-132; WSU-HIC-060907M1F
• First Posted: Aug 27, 2007
• Last Update Posted: May 4, 2022
• Last Verified: Apr 1, 2022

• Keywords provided by Jeffrey Zonder, Principal Investigator, Barbara Ann Karmanos Cancer Institute: primary systemic amyloidosis; light chain deposition disease
• Additional relevant MeSH terms: Immunoglobulin Light-chain Amyloidosis; Multiple Myeloma; Amyloidosis; Dexamethasone; Dexamethasone acetate; Bortezomib; Melphalan; Dexamethasone 21-phosphate; BB 1101

Study Results

Participant Flow

Arm/Group Title	Melphalan, Dexamethasone, Bortezomib,
Arm/Group Description	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 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
STARTED	35
COMPLETED	33
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Melphalan, Dexamethasone, Bortezomib,
Arm/Group Description	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 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 Participants	35
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

Title	Complete Hematologic Response
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

Individuals evaluable for response

Arm/Group Title	Melphalan, Dexamethasone, Bortezomib,
Arm/Group Description	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 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 Participants	33
Measure individuals	33
Number [participants]	16 45.7%

2. Secondary Outcome

Title	Overall Survival
Time Frame	Day 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

Title	Time to Treatment Failure
Time Frame	Day 1 of Each Cycle

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Change in Quality of Life From Baseline as Assessed by the Functional Assessment of Cancer Therapy-Neurotoxicity Questionnaire.
Time Frame	At the start of each cycle

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Organ Response Rate (OrR)
Time Frame	Beginning 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

Title	Toxicity, Including Neurotoxicity
Time Frame	Day 1 of Each Cycle

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Overall Hematologic Response Rate (OHR)
Time Frame	Beginning 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

Arm/Group Title	Melphalan, Dexamethasone, Bortezomib,
Arm/Group Description	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 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
Total	12/35 (34.3%)
Blood and lymphatic system disorders
thrombocytopenia	2/35 (5.7%)	2
Edema	2/35 (5.7%)	2
Cardiac disorders
Congestive Heart Failure	1/35 (2.9%)	1
Hypotension	1/35 (2.9%)	1
Ventricular Arrhythmia	2/35 (5.7%)	2
Hypertension	2/35 (5.7%)	2
cardiac Arrhythmia	1/35 (2.9%)	1
Gastrointestinal disorders
Dehydration	2/35 (5.7%)	2
Nausea	1/35 (2.9%)	1
Vomiting	1/35 (2.9%)	1
General disorders
Death	2/35 (5.7%)	2
Pain-chest wall	1/35 (2.9%)	1
Infections and infestations
Infection with Normal ANC-Lung (pneumonia)	2/35 (5.7%)	2
Infection with Normal ANC-Catheter related	1/35 (2.9%)	1
Infection with Normal ANC-Skin (cellulitis)-shingles	1/35 (2.9%)	1
Metabolism and nutrition disorders
Hyperglycemia	1/35 (2.9%)	1
Hyponatremia	1/35 (2.9%)	1
Creatinine	2/35 (5.7%)	2
Nervous system disorders
syncope	1/35 (2.9%)	1
Pain-Headache	2/35 (5.7%)	2
Psychiatric disorders
Mental Status Change	2/35 (5.7%)	2
Renal and urinary disorders
Renal Failure	1/35 (2.9%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/35 (5.7%)	2
Hypoxia	2/35 (5.7%)	2
Other (Not Including Serious) Adverse Events
	Melphalan, Dexamethasone, Bortezomib,
	Affected / at Risk (%)	# Events
Total	3/35 (8.6%)
Blood and lymphatic system disorders
Hemoglobin	2/35 (5.7%)	2
Gastrointestinal disorders
Constipation	2/35 (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.