Bendamustine and Dexamethasone in Patients With Relapsed AL Amyloidosis

• ClinicalTrials.gov Identifier: NCT01222260
• Recruitment Status: Completed
• First Posted: October 18, 2010
• Results First Posted: March 30, 2020
• Last Update Posted: March 30, 2020
• Sponsor: Columbia University
• Collaborator: Cephalon
• Information provided by (Responsible Party): Suzanne Lentzsch, MD, Columbia University

Study Description

Brief Summary:

The study is being done to see if the combination of bendamustine and dexamethasone will help people with amyloidosis that has returned after standard treatment, and to to estimate the partial hematologic response rate (PHR).

Condition or disease	Intervention/treatment	Phase
AL Amyloidosis	Drug: Bendamustine; Drug: Dexamethasone	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of the Combination of Bendamustine and Dexamethasone in Patients With Relapsed AL Amyloidosis
• Actual Study Start Date: January 2013
• Actual Primary Completion Date: March 2019
• Actual Study Completion Date: July 3, 2019

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment Arm; Subjects with AL will receive Bendamustine and Dexamethasone

Drug: Bendamustine; Patients will start bendamustine at dose level 0 and according to CrCl on day 1 and 2 of each cycle: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle; CrCl 59 - 30 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle Available to qualifying subjects is the option to dose escalate to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study); 100 mg/m2 (if CrCl 59-30 mL/min at the time of inclusion into the study); Other Names: Bendamustine Hydrochloride; Treanda ®; Drug: Dexamethasone; 40 mg orally on days 1, 8, 15, 22 of each cycle; Other Name: Decadron

Outcome Measures

Primary Outcome Measures :

1. Partial Hematologic Response (PHR) Rate [ Time Frame: Up to 2 years ]
   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.

Secondary Outcome Measures :

1. Overall Hematologic Response Rate (OHR) [ Time Frame: Up to 2 years ]
   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.
2. Organ Response Rate (ORR) [ Time Frame: Up to 2 years ]
   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.
3. Median Overall Survival (OS) [ Time Frame: Up to 2 years ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Massachusetts

Tufts Medical Center

Boston, Massachusetts, United States, 02111

Boston Medical Center

Boston, Massachusetts, United States, 02118

United States, Michigan

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, United States, 48201

United States, New York

Mt. Sinai Medical Center

New York, New York, United States, 10023

Columbia University

New York, New York, United States, 10032

Memorial Sloan-Kettering Cancer Center

New York, New York, United States, 10065

Sponsors and Collaborators

Columbia University

Cephalon

Investigators

• Principal Investigator: Suzanne Lentzsch, MD, PhD; Columbia University

  Study Documents (Full-Text)

Documents provided by Suzanne Lentzsch, MD, Columbia University:

Study Protocol and Statistical Analysis Plan  [PDF] March 3, 2015

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 May 1;38(13):1455-1462. doi: 10.1200/JCO.19.01721. Epub 2020 Feb 21.

• Responsible Party: Suzanne Lentzsch, MD, Associate Professor of Clinical Medicine, Columbia University
• ClinicalTrials.gov Identifier: NCT01222260
• Other Study ID Numbers: AAAJ7800; 10-012 (PRO10050217) ( Other Identifier: University of Pittsburgh )
• First Posted: October 18, 2010
• Results First Posted: March 30, 2020
• Last Update Posted: March 30, 2020
• Last Verified: March 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Deidentified individual participant data that underlie the reported results will be made available 3 months after publication for a period of 5 years after the publication.
• Supporting Materials: Study Protocol
• Time Frame: 3 months after manuscript publication for a period of 5 years after the publication.
• Access Criteria: Proposals for access should be sent to cancerclinicaltrials@cumc.columbia.edu.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Suzanne Lentzsch, MD, Columbia University:

Amyloidosis; Dexamethasone; Bendamustine; Relapsed AL Amyloidosis

Additional relevant MeSH terms:

Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Bendamustine Hydrochloride; Proteostasis Deficiencies; Metabolic Diseases; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Paraproteinemias; Dexamethasone; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action