First-line Pomalidomide, Bortezomib, and Dexamethasone For AL Amyloidosis or LCDD
Primary Purpose
Light Chain Deposition Disease, Primary Systemic Amyloidosis
Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
pomalidomide
bortezomib
dexamethasone
Laboratory Biomarker Analysis
Sponsored by
About this trial
This is an interventional treatment trial for Light Chain Deposition Disease
Eligibility Criteria
Inclusion Criteria:
- Understand and voluntarily sign an informed consent form
- Able to adhere to protocol requirements
- Histologically confirmed AL or LCDD (any time prior to screening)
- Up to 1 cycle of prior therapy allowed (maximum of 120 mg total dexamethasone (or equivalent amount of prednisone), 4 days of melphalan, and/or 4 doses of velcade; at least 4 wks has to have had passed since last dose of melphalan, 2 wks since last velcade or glucocorticoid dose
Measurable light chain elevation, as defined by:
- A difference between the involved immunoglobulin free light chain and uninvolved light chain and uninvolved light chain (dFLC) of >= 5 mg/dL AND abnormal serum immunoglobulin kappa lambda free light chain ratio
- EXCEPTION: during the DOSE ESCALATION PORTION of the study only, a measurable M-protein (>= 0.5 g/dL) on serum protein electrophoresis (SPEP) or a measurable urinary light chain (>= 200 mg/24 hrs) by urine protein electrophoresis (UPEP) without a dFLC meeting the above criteria is acceptable; subjects without a dFLC >= 5 mg/dL treated at the MTD will not count towards the expansion cohort
- Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 at study entry
- Demonstrated clonal population of plasma cells in the bone marrow or positive immunohistochemical stain with anti-light chain anti-sera of amyloid fibrils
- NTproBNP < 8500 pg/mL
- Absolute neutrophil count >= 1000/mm^3
- Platelet count >= 75,000/mm^3
- Serum creatinine =< 2.5 mg/dL
- Total bilirubin =< 1.5 mg/dL
- AST(SGOT) and ALT(SGPT) =< 3 x upper limit of normal (ULN)
- All study participants must be registered into the mandatory POMALYST REMS™ program, and be willing and able to comply with the requirements of the POMALYST REMS™ program
- Disease free of prior malignancies for > or = 2 years with exception of treated basal cell or squamous cell carcinoma of the skin. Carcinoma "in situ" of the cervix or breast, or low-risk localized prostate cancer does not outright exclude patients, but such cases need to be discussed with Dr. Zonder prior to enrollment.
- Females of childbearing potential (FCBP) must have negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to and again within 24 hours of starting pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking pomalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure
- Able to take aspirin (ASA;81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin), unless baseline prothrombin time [PT] or partial thromboplastin time [PTT] is >= 1.5 ULN, in which case thromboprophylaxis not required
Exclusion Criteria:
- Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
- Pregnant or breast feeding females; (lactating females must agree not to breast feed while taking pomalidomide)
- Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
- Use of any other experimental drug or therapy within 28 days of baseline
- Known hypersensitivity reaction or history of desquamating rash related to thalidomide or lenalidomide
- Known hypersensitivity to bortezomib, boron, or any of the other agents utilized in this protocol
- Patient has >= grade 3 peripheral sensory neuropathy or >= grade 2 painful sensory neuropathy within 14 days before enrollment; (NOTE: patient with peripheral neuropathy [PN] that was previously this severe but is currently improved due to ongoing therapy [e.g., gabapentin or amitriptyline] may be 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 as not medically relevant); note: there is no lower limit of left ventricular ejection fraction below which patients are excluded from participation
- Concurrent use of other anti-cancer agents or treatments
- Known positive for human immunodeficiency virus (HIV) or infectious hepatitis, type A, B or C
Meets criteria for symptomatic multiple myeloma, defined as:
>= 10% monoclonal plasma cells in the marrow AND ANY OF THE FOLLOWING:
- Biopsy-confirmed plasmacytoma
- Lytic bone lesion(s)
- Hypercalcemia without other explanation
Sites / Locations
- Colorado Blood Cancer Institute
- Boston University School of Medicine
- Barbara Ann Karmanos Cancer Institute
- Duke University Medical Center
- Princess Margaret Cancer Centre
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment (pomalidomide, bortezomib, and dexamethasone)
Arm Description
Patients receive pomalidomide PO on days 1-21; bortezomib IV or SC on days 1, 8, and 15; and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Outcomes
Primary Outcome Measures
Maximum tolerated dose defined as the dose level before 2 of 6 patients experience dose-limiting toxicity (DLT) using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Secondary Outcome Measures
Complete hematologic response rate (hCR)
Will be estimated and reported with 95% confidence intervals.
Overall hematologic response rate (partial response [PR] + complete response [CR])
Organ response rates (heart, liver, kidney)
Organ responses will be tabulated and reported for all patients with cardiac, renal, hepatic, and/or neurologic involvement by amyloidosis.
Overall survival
Will be estimated and reported with 95% confidence interval.
Progression free survival
Will be estimated and reported with 95% confidence interval.
Full Information
NCT ID
NCT01728259
First Posted
November 13, 2012
Last Updated
May 5, 2023
Sponsor
Barbara Ann Karmanos Cancer Institute
1. Study Identification
Unique Protocol Identification Number
NCT01728259
Brief Title
First-line Pomalidomide, Bortezomib, and Dexamethasone For AL Amyloidosis or LCDD
Official Title
Phase I Study of Pomalidomide, Bortezomib, and Dexamethasone (PVD) as First-Line Treatment of AL Amyloidosis or Light Chain Deposition Disease
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Terminated
Why Stopped
FDA placed the study on a clinical hold, due to the concerns by the FDA and Health Canada, Celgene decided to permanently close the study.
Study Start Date
March 2013 (Actual)
Primary Completion Date
October 31, 2018 (Actual)
Study Completion Date
October 31, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Barbara Ann Karmanos Cancer Institute
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This phase I trial studies the side effects and best dose of pomalidomide and bortezomib when given together with dexamethasone in treating patients with amyloid light-chain amyloidosis or light chain deposition disease. Biological therapies, such as pomalidomide, may stimulate the immune system in different ways and stop abnormal cells from growing. Bortezomib may stop the growth of abnormal cells by blocking some of the enzymes needed for cell growth. Giving pomalidomide and bortezomib together with dexamethasone may be an effective treatment for amyloid light-chain amyloidosis or light chain deposition disease
Detailed Description
PRIMARY OBJECTIVES:
I. Establish the maximum tolerated dose (MTD) of the combination of pomalidomide, bortezomib, and dexamethasone (PVD) to take forward in a subsequent phase 2 study.
SECONDARY OBJECTIVES:
I. Obtain a preliminary assessment of efficacy of PVD regimen as initial treatment of amyloid light-chain (AL) or light chain deposition disease (LCDD).
OUTLINE: This is a dose-escalation study of pomalidomide and bortezomib.
Patients receive pomalidomide orally (PO) on days 1-21; bortezomib intravenously (IV) on days 1, 8, and 15; and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at least every 3 months.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Light Chain Deposition Disease, Primary Systemic Amyloidosis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment (pomalidomide, bortezomib, and dexamethasone)
Arm Type
Experimental
Arm Description
Patients receive pomalidomide PO on days 1-21; bortezomib IV or SC on days 1, 8, and 15; and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
pomalidomide
Other Intervention Name(s)
CC-4047
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
bortezomib
Other Intervention Name(s)
LDP 341, MLN341, VELCADE
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
dexamethasone
Other Intervention Name(s)
Aeroseb-Dex, Decaderm, Decadron, DM, DXM
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Maximum tolerated dose defined as the dose level before 2 of 6 patients experience dose-limiting toxicity (DLT) using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time Frame
28 days
Secondary Outcome Measure Information:
Title
Complete hematologic response rate (hCR)
Description
Will be estimated and reported with 95% confidence intervals.
Time Frame
Up to 28 days
Title
Overall hematologic response rate (partial response [PR] + complete response [CR])
Time Frame
Up to 28 days
Title
Organ response rates (heart, liver, kidney)
Description
Organ responses will be tabulated and reported for all patients with cardiac, renal, hepatic, and/or neurologic involvement by amyloidosis.
Time Frame
Up to 28 days
Title
Overall survival
Description
Will be estimated and reported with 95% confidence interval.
Time Frame
From date of registration to date of death, assessed up to 28 days
Title
Progression free survival
Description
Will be estimated and reported with 95% confidence interval.
Time Frame
Up to 28 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Understand and voluntarily sign an informed consent form
Able to adhere to protocol requirements
Histologically confirmed AL or LCDD (any time prior to screening)
Up to 1 cycle of prior therapy allowed (maximum of 120 mg total dexamethasone (or equivalent amount of prednisone), 4 days of melphalan, and/or 4 doses of velcade; at least 4 wks has to have had passed since last dose of melphalan, 2 wks since last velcade or glucocorticoid dose
Measurable light chain elevation, as defined by:
A difference between the involved immunoglobulin free light chain and uninvolved light chain and uninvolved light chain (dFLC) of >= 5 mg/dL AND abnormal serum immunoglobulin kappa lambda free light chain ratio
EXCEPTION: during the DOSE ESCALATION PORTION of the study only, a measurable M-protein (>= 0.5 g/dL) on serum protein electrophoresis (SPEP) or a measurable urinary light chain (>= 200 mg/24 hrs) by urine protein electrophoresis (UPEP) without a dFLC meeting the above criteria is acceptable; subjects without a dFLC >= 5 mg/dL treated at the MTD will not count towards the expansion cohort
Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 at study entry
Demonstrated clonal population of plasma cells in the bone marrow or positive immunohistochemical stain with anti-light chain anti-sera of amyloid fibrils
NTproBNP < 8500 pg/mL
Absolute neutrophil count >= 1000/mm^3
Platelet count >= 75,000/mm^3
Serum creatinine =< 2.5 mg/dL
Total bilirubin =< 1.5 mg/dL
AST(SGOT) and ALT(SGPT) =< 3 x upper limit of normal (ULN)
All study participants must be registered into the mandatory POMALYST REMS™ program, and be willing and able to comply with the requirements of the POMALYST REMS™ program
Disease free of prior malignancies for > or = 2 years with exception of treated basal cell or squamous cell carcinoma of the skin. Carcinoma "in situ" of the cervix or breast, or low-risk localized prostate cancer does not outright exclude patients, but such cases need to be discussed with Dr. Zonder prior to enrollment.
Females of childbearing potential (FCBP) must have negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to and again within 24 hours of starting pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking pomalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure
Able to take aspirin (ASA;81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin), unless baseline prothrombin time [PT] or partial thromboplastin time [PTT] is >= 1.5 ULN, in which case thromboprophylaxis not required
Exclusion Criteria:
Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
Pregnant or breast feeding females; (lactating females must agree not to breast feed while taking pomalidomide)
Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
Use of any other experimental drug or therapy within 28 days of baseline
Known hypersensitivity reaction or history of desquamating rash related to thalidomide or lenalidomide
Known hypersensitivity to bortezomib, boron, or any of the other agents utilized in this protocol
Patient has >= grade 3 peripheral sensory neuropathy or >= grade 2 painful sensory neuropathy within 14 days before enrollment; (NOTE: patient with peripheral neuropathy [PN] that was previously this severe but is currently improved due to ongoing therapy [e.g., gabapentin or amitriptyline] may be 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 as not medically relevant); note: there is no lower limit of left ventricular ejection fraction below which patients are excluded from participation
Concurrent use of other anti-cancer agents or treatments
Known positive for human immunodeficiency virus (HIV) or infectious hepatitis, type A, B or C
Meets criteria for symptomatic multiple myeloma, defined as:
>= 10% monoclonal plasma cells in the marrow AND ANY OF THE FOLLOWING:
Biopsy-confirmed plasmacytoma
Lytic bone lesion(s)
Hypercalcemia without other explanation
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeffrey Zonder
Organizational Affiliation
Barbara Ann Karmanos Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Colorado Blood Cancer Institute
City
Denver
State/Province
Colorado
ZIP/Postal Code
80218
Country
United States
Facility Name
Boston University School of Medicine
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02118-2393
Country
United States
Facility Name
Barbara Ann Karmanos Cancer Institute
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Princess Margaret Cancer Centre
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
12. IPD Sharing Statement
Learn more about this trial
First-line Pomalidomide, Bortezomib, and Dexamethasone For AL Amyloidosis or LCDD
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