Back to resultsLow-Dose Azacitidine, Lenalidomide, and Low-Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma
Primary Purpose
Refractory Multiple Myeloma
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
azacitidine
lenalidomide
dexamethasone
DNA methylation analysis
gene expression analysis
bone marrow aspiration
immunohistochemistry staining method
reverse transcriptase-polymerase chain reaction
flow cytometry
Sponsored by
About this trial
This is an interventional treatment trial for Refractory Multiple Myeloma
Eligibility Criteria
Inclusion Criteria:
- Understand and voluntarily sign an informed consent form
- Able to adhere to the study visit schedule and other protocol requirements
- Refractory or relapsed multiple myeloma
- Measurable disease defined as at least one of the following: Serum m-spike ≥ 1g/dL, urine m-spike ≥ 200mg/24hrs, serum free light chains ≥ 100mg/L (provided the kappa/lambda ratio is abnormal), or bone marrow plasma cells ≥ 30%
- Previous therapy with IMiD™ compounds (thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (bortezomib, carfilzomib), and corticosteroids must be discontinued at least 14 days before entry onto this study.
- Previous cytotoxic chemotherapy (e.g. alkylating chemotherapy, anthracyclines, and vinca alkaloids), radiation therapy to the pelvis, and any experimental therapy other than carfilzomib or pomalidomide must have been discontinued at least 28 days prior to entry onto this study.
- Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 at study entry.
Laboratory test results within these ranges:
- Absolute neutrophil count ≥ 1,500 /mm³
- Platelet count ≥ 75,000/mm³
- Calculated creatinine clearance (Cockcroft-Gault) ≥ 30ml/min.
- Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
- Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) levels ≤2 x ULN
- All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.
- Females of childbearing potential (FCBP)must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 days) 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 lenalidomide. 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 successful vasectomy.
- Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin) if no additional risk factor for venous thromboembolic event (VTE) other than myeloma diagnosis according to IMW guidelines
- Able to take low molecular weight heparin or warfarin if ≥ 1 additional risk factor for VTE according to IMW guidelines
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 lenalidomide or azacitidine)
- 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 experimental drug or therapy other than carfilzomib and pomalidomide within 28 days of treatment start on this protocol.
- Neuropathy > Grade 2
- Known hypersensitivity to thalidomide, lenalidomide, azacitidine, or mannitol
- The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or lenalidomide drugs
- Concurrent use of other anti-cancer agents or treatments, concurrent radiation to the pelvis. Palliative radiation to areas outside the pelvis is allowed
- Previous inability to tolerate full-dose lenalidomide, adjusted to creatinine clearance (CrCl) according to Cockcroft-Gault at the time of previous lenalidomide treatment (25mg day 1-21 every 28 days if CrCl > 60ml/min, 10mg lenalidomide d1-21 every 28 days if CrCl < 60mL/min but > 30mL/min, lenalidomide 15mg every 48 h d1-21 every 28 days if CrCl < 30mL/min but not requiring dialysis, lenalidomide 5mg daily, day 1-21 every 28 days if CrCl < 30mL/min and requiring dialysis).
Sites / Locations
- University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
- Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Arm A - Azacitidine/Lenalidomide/Dexamethasone
Arm B - Chronic Kidney Disease (CDK) Cohort
Arm Description
Dose Level (DL) 1 - Azacitidine 30mg/m2 1x week + Lenalidomide 25mg d1-21 every 28d + Dexamethasone 40mg once a week DL 2 - Azacitidine 40mg/m2 1x week + Lenalidomide 25mg d1-21 every 28d + Dexamethasone 40mg once a week DL 3 - Azacitidine 30mg/m2 2x week + Lenalidomide 25mg d1-21 every 28d + Dexamethasone 40mg once a week DL 4 - Azacitidine 40mg/m2 2x week + Lenalidomide 25mg d1-21 every 28d + Dexamethasone 40mg once a week DL 5 - Azacitidine 50mg/m2 2x week + Lenalidomide 25mg d1-21 every 28d + Dexamethasone 40mg once a week Patients (with GFR > 60 ml/min) receive azacitidine subcutaneously 1 or 2x per weekly and oral Dexamethasone 1x weekly starting on day 1. Patients receive oral lenalidomide 1x daily on days 1-21. Treatment repeats every 28 days for 6 courses. Patients then continue to receive lenalidomide as maintenance therapy. Treatment continues in the absence of disease progression or unacceptable toxicity.
DL (-1) - Azacitidine 30mg/m2 2x week + Lenalidomide 10mg d1-21 every 28d + Dexamethasone 40mg once a week DL 1 - Azacitidine 40mg/m2 2x week + Lenalidomide 10mg d1-21 every 28d + Dexamethasone 40mg once a week DL 2 - Azacitidine 50mg/m2 2x week + Lenalidomide 10mg d1-21 every 28d + Dexamethasone 40mg once a week Patients (with GFR 30-59 ml/min Chronic Kidney Disease (CKD)) receive azacitidine subcutaneously 1 or 2x per weekly and oral dexamethasone 1x weekly starting on day 1. Patients receive oral lenalidomide 1x daily on days 1-21. Treatment repeats every 28 days for 6 courses. Patients then continue to receive lenalidomide as maintenance therapy. Treatment continues in the absence of disease progression or unacceptable toxicity.
Outcomes
Primary Outcome Measures
Phase I: Highest Tolerated Low Dose (HTLD)
Azacitidine given at low but increasing doses up to 50mg/m2 twice a week. Maximum tolerated dose reported.
Secondary Outcome Measures
Percent of Participants With Clinical Benefit and Response According to International Response Criteria
Percent of participants with response according to international response criteria (>= PR) and percent of participants with clinical benefit response (>= minor response according to adapted EBMT criteria). Determined with serum and 24 hour urine protein electrophoresis, and as appropriate, supplemented by immunofixation, serum free light chain assay, and bone marrow examination. Response before high dose melphalan and autologous stem cell transplant will also be confirmed by two separate blood and 24 hour urine tests between the last dose of combination therapy and the first dose of the mobilizing agent.
Percent of Participants With Clinical Benefit and Response According to International Response Criteria
Percent of participants with response according to international response criteria (>= PR) and percent of participants with clinical benefit response (>= minor response according to adapted EBMT criteria). Determined with serum and 24 hour urine protein electrophoresis, and as appropriate, supplemented by immunofixation, serum free light chain assay, and bone marrow examination. Response before high dose melphalan and autologous stem cell transplant will also be confirmed by two separate blood and 24 hour urine tests between the last dose of combination therapy and the first dose of the mobilizing agent.
Median Progression-free Survival (PFS)
Median PFS, measured in months from study entry to progression as defined by international response criteria or death of any cause, whichever comes first
Overall Survival
Overall survival will be measured from study entry to death from any cause - median months survival will be reported
Full Information
NCT ID
NCT01155583
First Posted
June 30, 2010
Last Updated
October 20, 2020
Sponsor
Case Comprehensive Cancer Center
1. Study Identification
Unique Protocol Identification Number
NCT01155583
Brief Title
Low-Dose Azacitidine, Lenalidomide, and Low-Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma
Official Title
A Phase I/II Trial Of Very Low to Low-Doses of Continuous Azacitidine in Combination With Standard Doses of Lenalidomide and Low-Dose Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma
Study Type
Interventional
2. Study Status
Record Verification Date
October 2020
Overall Recruitment Status
Completed
Study Start Date
June 2010 (undefined)
Primary Completion Date
May 28, 2016 (Actual)
Study Completion Date
November 6, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Case Comprehensive Cancer Center
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
RATIONALE: Drugs used in chemotherapy, such as azacitidine and dexamethasone, work in different ways to stop the growth of cancer cells either by killing the cells or by stopping them from dividing. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Giving azacitidine together with lenalidomide and dexamethasone may kill more cancer cells.
PURPOSE: This phase I/II trial is studying the side effects and best dose of azacitidine when given together with lenalidomide and low-dose dexamethasone in treating patients with relapsed or refractory multiple myeloma.
Detailed Description
PRIMARY OBJECTIVES:
Define the highest tolerated low dose (HTLD) and safety of azacitidine given at low but increasing doses up to 50mg/m2 twice a week concurrently with Glomerular filtration rate (GFR)-adjusted lenalidomide and low dose dexamethasone in patients with relapsed or refractory multiple myeloma.
SECONDARY OBJECTIVES:
Response according to international response criteria (≥PR) and clinical benefit response (≥minor response according to adapted EBMT criteria)
Correlate response with plasma activity of the azacitidine inactivating enzyme cytidine deaminase (CDA)
Progression-free survival and overall survival
Peripheral blood hematopoietic progenitor (CD34+) yield and time to neutrophil and platelet recovery in patients undergoing autologous stem cell transplantation
Promoter demethylation and gene reactivation in myeloma cells and hematopoietic progenitors treated at the HTLD / HTLD-CKD level after cycle 1
Changes in global gene expression in myeloma cells treated at the HTLD / HTLD-CKD level after cycle 1
OUTLINE:
This is a phase I, dose-escalation study of azacitidine followed by a phase II study.
Patients receive azacitidine subcutaneously once or twice weekly and oral dexamethasone once weekly starting on day 1. Patients also receive oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 6 courses. Patients then continue to receive lenalidomide as maintenance therapy. Treatment continues in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 3 years.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Refractory Multiple Myeloma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
45 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Arm A - Azacitidine/Lenalidomide/Dexamethasone
Arm Type
Experimental
Arm Description
Dose Level (DL) 1 - Azacitidine 30mg/m2 1x week + Lenalidomide 25mg d1-21 every 28d + Dexamethasone 40mg once a week
DL 2 - Azacitidine 40mg/m2 1x week + Lenalidomide 25mg d1-21 every 28d + Dexamethasone 40mg once a week
DL 3 - Azacitidine 30mg/m2 2x week + Lenalidomide 25mg d1-21 every 28d + Dexamethasone 40mg once a week
DL 4 - Azacitidine 40mg/m2 2x week + Lenalidomide 25mg d1-21 every 28d + Dexamethasone 40mg once a week
DL 5 - Azacitidine 50mg/m2 2x week + Lenalidomide 25mg d1-21 every 28d + Dexamethasone 40mg once a week
Patients (with GFR > 60 ml/min) receive azacitidine subcutaneously 1 or 2x per weekly and oral Dexamethasone 1x weekly starting on day 1. Patients receive oral lenalidomide 1x daily on days 1-21. Treatment repeats every 28 days for 6 courses. Patients then continue to receive lenalidomide as maintenance therapy. Treatment continues in the absence of disease progression or unacceptable toxicity.
Arm Title
Arm B - Chronic Kidney Disease (CDK) Cohort
Arm Type
Experimental
Arm Description
DL (-1) - Azacitidine 30mg/m2 2x week + Lenalidomide 10mg d1-21 every 28d + Dexamethasone 40mg once a week
DL 1 - Azacitidine 40mg/m2 2x week + Lenalidomide 10mg d1-21 every 28d + Dexamethasone 40mg once a week
DL 2 - Azacitidine 50mg/m2 2x week + Lenalidomide 10mg d1-21 every 28d + Dexamethasone 40mg once a week
Patients (with GFR 30-59 ml/min Chronic Kidney Disease (CKD)) receive azacitidine subcutaneously 1 or 2x per weekly and oral dexamethasone 1x weekly starting on day 1. Patients receive oral lenalidomide 1x daily on days 1-21. Treatment repeats every 28 days for 6 courses. Patients then continue to receive lenalidomide as maintenance therapy. Treatment continues in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
azacitidine
Other Intervention Name(s)
5-AC, 5-azacytidine, 5-AZC, azacytidine, ladakamycin, Vidaza
Intervention Description
Given by subcutaneous injection (SC)
Intervention Type
Drug
Intervention Name(s)
lenalidomide
Other Intervention Name(s)
CC-5013, IMiD-1, Revlimid
Intervention Description
Given orally
Intervention Type
Drug
Intervention Name(s)
dexamethasone
Other Intervention Name(s)
Aeroseb-Dex, Decaderm, Decadron, Decaspray, DM, DXM
Intervention Description
Given orally
Intervention Type
Other
Intervention Name(s)
DNA methylation analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
gene expression analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
bone marrow aspiration
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
immunohistochemistry staining method
Other Intervention Name(s)
immunohistochemistry
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
reverse transcriptase-polymerase chain reaction
Other Intervention Name(s)
RT-PCR
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
flow cytometry
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Phase I: Highest Tolerated Low Dose (HTLD)
Description
Azacitidine given at low but increasing doses up to 50mg/m2 twice a week. Maximum tolerated dose reported.
Time Frame
During the first 28-day cycle
Secondary Outcome Measure Information:
Title
Percent of Participants With Clinical Benefit and Response According to International Response Criteria
Description
Percent of participants with response according to international response criteria (>= PR) and percent of participants with clinical benefit response (>= minor response according to adapted EBMT criteria). Determined with serum and 24 hour urine protein electrophoresis, and as appropriate, supplemented by immunofixation, serum free light chain assay, and bone marrow examination. Response before high dose melphalan and autologous stem cell transplant will also be confirmed by two separate blood and 24 hour urine tests between the last dose of combination therapy and the first dose of the mobilizing agent.
Time Frame
at 6 months
Title
Percent of Participants With Clinical Benefit and Response According to International Response Criteria
Description
Percent of participants with response according to international response criteria (>= PR) and percent of participants with clinical benefit response (>= minor response according to adapted EBMT criteria). Determined with serum and 24 hour urine protein electrophoresis, and as appropriate, supplemented by immunofixation, serum free light chain assay, and bone marrow examination. Response before high dose melphalan and autologous stem cell transplant will also be confirmed by two separate blood and 24 hour urine tests between the last dose of combination therapy and the first dose of the mobilizing agent.
Time Frame
at 12 months
Title
Median Progression-free Survival (PFS)
Description
Median PFS, measured in months from study entry to progression as defined by international response criteria or death of any cause, whichever comes first
Time Frame
Up to 3 years
Title
Overall Survival
Description
Overall survival will be measured from study entry to death from any cause - median months survival will be reported
Time Frame
up to 3 years
Other Pre-specified Outcome Measures:
Title
Changes in Global Gene Expression
Description
The RNA harvested from myeloma cells before and after the first cycle of therapy at the HTLD level will furthermore be used to identify changes in global gene expression using the Illumina® HT12 array.
Time Frame
before and after the first cycle of therapy
Title
Quantify the Activity of Azacitidine Inactivating Enzyme Cytidine Deaminase (CDA)
Description
Plasma from peripheral blood draws will be used to quantify the activity of CDA using an HPLC method.The enzymatic activity is determined by comparison of cytidine deamination achieved by plasma samples with deamination achieved by incubation of cytidine with dilutions of pure CDA enzyme standards.
Time Frame
at 6 months
Title
Promoter Demethylation and Gene Reactivation
Description
Promoter demethylation and gene reactivation will be measured at least at the HTLD level using the Illumina® HumanMethylation27 BeadChip array on CD138 purified and CD34 purified cells obtained from bone marrow aspirates
Time Frame
within 7 days before treatment start and at the end of cycle #1
Title
CD34+ Cell Yield and Time to Neutrophil and Platelet Recovery
Description
CD34+ cell yield will be calculated based on flow cytometry of mononuclear cells harvested following stem cell mobilization. Time to neutrophil (> 1,000/mm3) and platelet (> 100,000/mm3) recovery will be counted from the day of stem cell infusion (=day 0)
Time Frame
after cycle 1 (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 the study visit schedule and other protocol requirements
Refractory or relapsed multiple myeloma
Measurable disease defined as at least one of the following: Serum m-spike ≥ 1g/dL, urine m-spike ≥ 200mg/24hrs, serum free light chains ≥ 100mg/L (provided the kappa/lambda ratio is abnormal), or bone marrow plasma cells ≥ 30%
Previous therapy with IMiD™ compounds (thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (bortezomib, carfilzomib), and corticosteroids must be discontinued at least 14 days before entry onto this study.
Previous cytotoxic chemotherapy (e.g. alkylating chemotherapy, anthracyclines, and vinca alkaloids), radiation therapy to the pelvis, and any experimental therapy other than carfilzomib or pomalidomide must have been discontinued at least 28 days prior to entry onto this study.
Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 at study entry.
Laboratory test results within these ranges:
Absolute neutrophil count ≥ 1,500 /mm³
Platelet count ≥ 75,000/mm³
Calculated creatinine clearance (Cockcroft-Gault) ≥ 30ml/min.
Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) levels ≤2 x ULN
All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.
Females of childbearing potential (FCBP)must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 days) 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 lenalidomide. 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 successful vasectomy.
Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin) if no additional risk factor for venous thromboembolic event (VTE) other than myeloma diagnosis according to IMW guidelines
Able to take low molecular weight heparin or warfarin if ≥ 1 additional risk factor for VTE according to IMW guidelines
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 lenalidomide or azacitidine)
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 experimental drug or therapy other than carfilzomib and pomalidomide within 28 days of treatment start on this protocol.
Neuropathy > Grade 2
Known hypersensitivity to thalidomide, lenalidomide, azacitidine, or mannitol
The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or lenalidomide drugs
Concurrent use of other anti-cancer agents or treatments, concurrent radiation to the pelvis. Palliative radiation to areas outside the pelvis is allowed
Previous inability to tolerate full-dose lenalidomide, adjusted to creatinine clearance (CrCl) according to Cockcroft-Gault at the time of previous lenalidomide treatment (25mg day 1-21 every 28 days if CrCl > 60ml/min, 10mg lenalidomide d1-21 every 28 days if CrCl < 60mL/min but > 30mL/min, lenalidomide 15mg every 48 h d1-21 every 28 days if CrCl < 30mL/min but not requiring dialysis, lenalidomide 5mg daily, day 1-21 every 28 days if CrCl < 30mL/min and requiring dialysis).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Frederic Reu
Organizational Affiliation
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ehsan Malek, MD
Organizational Affiliation
University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Low-Dose Azacitidine, Lenalidomide, and Low-Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma
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