- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01222260
Bendamustine and Dexamethasone in Patients With Relapsed AL Amyloidosis
Phase II Study of the Combination of Bendamustine and Dexamethasone in Patients With Relapsed AL Amyloidosis
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Systemic light-chain amyloidosis (AL) is a protein conformation disorder due to a clonal plasma cell dyscrasia. There are no established and approved second-line therapies for patients with systemic AL amyloidosis who fail initial melphalan-based treatment, be it high-dose melphalan with stem cell transplant or oral melphalan and dexamethasone (MDex). Therefore new treatments are needed for those who fail initial therapy and for those who initially respond but subsequently relapse.
Therapy of AL is generally based on treatment regimens used in multiple myeloma (MM). Bendamustine achieves partial response with relapsed/refractory MM. Based on this high anti-MM activity, we anticipate that bendamustine will also be very active in clonal plasma cell disorder associated with AL.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
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Massachusetts
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Boston, Massachusetts, United States, 02111
- Tufts Medical Center
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Boston, Massachusetts, United States, 02118
- Boston Medical Center
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Michigan
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Detroit, Michigan, United States, 48201
- Barbara Ann Karmanos Cancer Institute
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New York
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New York, New York, United States, 10032
- Columbia University
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New York, New York, United States, 10065
- Memorial Sloan-Kettering Cancer Center
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New York, New York, United States, 10023
- Mt. Sinai Medical Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Male or female patients aged ≥ 18 years old
- Histopathology of amyloidosis or light chain deposition disease based on detection by polarizing microscopy of green bi-refringent material in Congo red-stained tissue specimens or characteristic electron microscopy appearance or immunohistochemical stain with anti-light chain anti-sera
Demonstrate 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/dL in a 24 hr urine electrophoresis
- Serum immunoglobulin free light chain ≥ 5 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio. The difference between involved and uninvolved free light chains should be ≥ 5 mg/dL (dFLC)
- Demonstrate clonal population of plasma cells in the bone marrow or immunohistochemical stain with anti-light chain anti-sera of amyloid fibrils
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
- Patients had at least one prior regimen consisting of at least 1 cycle
- If not previously transplanted, patient should be either ineligible for autologous stem cell transplantation (ASCT), or must have declined the option of ASCT. Patients who have previously had ASCT and have subsequently progressed are eligible, provided other entry criteria are met
- Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
Patients must meet the following laboratory criteria:
- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
- Hemoglobin ≥ 9 g/dl (May transfuse packed red blood cells (PRBC) to meet parameter)
- Platelets ≥ 100x 10^9/L (Must be independent of platelet transfusion)
- Calculated creatinine clearance (CrCl) greater than or equal to 30 mL/min (Cockcroft-Gault Formula )
- Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN)
- Serum bilirubin <1.5 x ULN
- Serum potassium within normal limits
- Total serum calcium (corrected for serum albumin) or ionized calcium ≤ ULN
Exclusion Criteria:
- Patients meeting the criteria for symptomatic MM:
- Lytic lesions on skeletal survey or plasmacytoma
Patients meeting International Myeloma Working Group definition of symptomatic myeloma with symptoms only related to associated amyloidosis who would otherwise only meet the criteria for smoldering MM are potentially eligible
- Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure uncontrolled angina, severe uncontrolled ventricular arrhythmias, or
- electrocardiographic evidence of acute ischemia or active conduction system abnormalities (not including 1st degree atrioventricular (AV)-block, Wenckebach type 2nd degree heart block, or left bundle branch block. Prior to study entry, any electrocardiogram (ECG) abnormality at Screening has to be documented by the investigator or an authorized physician sub-investigator as not medically relevant). Note: There is no lower limit of left ventricular ejection fraction below which patients are excluded from participation.
- Patients with N-terminal (NT)-proBNP ≥ 1800nb/L or B-type natriuretic peptide (BNP) ≥ 400 ng/L, abnormal cardiac troponin T (cTnT) or cardiac troponin l (cTnI)
- Patient has received other investigational drugs within 14 days prior to enrollment
- Any form of secondary / familial amyloidosis
- Serious concurrent illness, which in the opinion of the investigator or an authorized physician sub-investigator would interfere with participation in this clinical study,
- Known HIV infection.
- Inability to provide informed consent or to comply with the schedule of office and treatment visits
- Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women(woman not of child-bearing potential is defined as any woman whose menstrual periods have stopped in the past 12 consecutive months or have had a complete hysterectomy or both ovaries surgically removed).
- Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, low-risk prostate cancer, or cancer after curative treatment.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment Arm
Subjects with AL will receive Bendamustine and Dexamethasone
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Patients will start bendamustine at dose level 0 and according to CrCl on day 1 and 2 of each cycle:
Available to qualifying subjects is the option to dose escalate to dose level (+)1:
Other Names:
40 mg orally on days 1, 8, 15, 22 of each cycle
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Partial Hematologic Response (PHR) Rate
Time Frame: Up to 2 years
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Only patients who have received at least 2 cycles of therapy are eligible for response assessment.
The proportion of patients with PHR two months post-treatment will be estimated, with a 95% exact binomial confidence interval.
Partial response is defined as the reduction of the difference between involved and uninvolved free light chains (dFLC) of ≥ 50% OR a reduction of ≥ 50% of the M-protein if M-spike is ≥ 0.5 g/dL.
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Up to 2 years
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Overall Hematologic Response Rate (OHR)
Time Frame: Up to 2 years
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The proportion of response-evaluable patients experiencing OHR will be estimated, with a 95% exact binomial confidence interval.
Overall hematologic response rate as defined by normalization of the free light chain levels and ratio, negative serum and urine immunofixation OR reduction in the difference between involved and uninvolved free light chains (dFLC) to <4 mg/dL.
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Up to 2 years
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Organ Response Rate (ORR)
Time Frame: Up to 2 years
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The proportion of response-evaluable patients experiencing ORR will be estimated, with a 95% exact binomial confidence interval.
Amyloid-related organ response will be evaluated on the basis of the accepted criteria described: Kidneys: 30% reduction or drop below 0.5 g in 24-hour urine protein excretion in the absence of progressive renal insufficiency.
Heart: N-terminal pro b-type natriuretic peptide (NT-proBNP) or B-type natriuretic peptide response (>30% and >300 ng/L decrease in patients with baseline NT-proBNP ≥ 650 ng/L or New York Heart Association (NYHA) class response (≥ 2 class decrease in subjects with baseline NYHA class 3 or 4).
Liver: 50% decrease of an initially elevated alkaline phosphatase level or reduction in the size of the liver by at least 2 cm.
Neuropathy: improvement supported by clinical history, neurologic exam, orthostatic vital signs, resolution of severe constipation or reduction of diarrhea to less than 50% of previous movements/day.
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Up to 2 years
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Median Overall Survival (OS)
Time Frame: Up to 2 years
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Survival is assessed as time to death from first day of treatment The OS function for response-evaluable will be estimated using the product-limit (Kaplan-Meier) estimator, along with 95% confidence bounds.
The median survival will be estimated from the survival function.
The analysis will be repeated on all patients who receive any therapy.
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Up to 2 years
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Suzanne Lentzsch, MD, PhD, Columbia University
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Metabolic Diseases
- Immune System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Lymphoproliferative Disorders
- Immunoproliferative Disorders
- Paraproteinemias
- Proteostasis Deficiencies
- Neoplasms, Plasma Cell
- Immunoglobulin Light-chain Amyloidosis
- Amyloidosis
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Autonomic Agents
- Peripheral Nervous System Agents
- Anti-Inflammatory Agents
- Antineoplastic Agents
- Antiemetics
- Gastrointestinal Agents
- Glucocorticoids
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Antineoplastic Agents, Hormonal
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Dexamethasone
- Bendamustine Hydrochloride
Other Study ID Numbers
- AAAJ7800
- 10-012 (PRO10050217) (Other Identifier: University of Pittsburgh)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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