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Low-Dose Azacitidine, Lenalidomide, and Low-Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT01155583
Recruitment Status : Completed
First Posted : July 2, 2010
Results First Posted : October 12, 2020
Last Update Posted : November 16, 2020
Sponsor:
Information provided by (Responsible Party):
Case Comprehensive Cancer Center

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.


Condition or disease Intervention/treatment Phase
Refractory Multiple Myeloma Drug: azacitidine Drug: lenalidomide Drug: dexamethasone Other: DNA methylation analysis Other: gene expression analysis Other: bone marrow aspiration Other: immunohistochemistry staining method Other: reverse transcriptase-polymerase chain reaction Other: flow cytometry Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 45 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : June 2010
Actual Primary Completion Date : May 28, 2016
Actual Study Completion Date : November 6, 2018


Arm Intervention/treatment
Experimental: Arm A - Azacitidine/Lenalidomide/Dexamethasone

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.

Drug: azacitidine
Given by subcutaneous injection (SC)
Other Names:
  • 5-AC
  • 5-azacytidine
  • 5-AZC
  • azacytidine
  • ladakamycin
  • Vidaza

Drug: lenalidomide
Given orally
Other Names:
  • CC-5013
  • IMiD-1
  • Revlimid

Drug: dexamethasone
Given orally
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • Decaspray
  • DM
  • DXM

Other: DNA methylation analysis
Correlative studies

Other: gene expression analysis
Correlative studies

Other: bone marrow aspiration
Correlative studies

Other: immunohistochemistry staining method
Correlative studies
Other Name: immunohistochemistry

Other: reverse transcriptase-polymerase chain reaction
Correlative studies
Other Name: RT-PCR

Other: flow cytometry
Correlative studies

Experimental: Arm B - Chronic Kidney Disease (CDK) Cohort

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.

Drug: azacitidine
Given by subcutaneous injection (SC)
Other Names:
  • 5-AC
  • 5-azacytidine
  • 5-AZC
  • azacytidine
  • ladakamycin
  • Vidaza

Drug: lenalidomide
Given orally
Other Names:
  • CC-5013
  • IMiD-1
  • Revlimid

Drug: dexamethasone
Given orally
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • Decaspray
  • DM
  • DXM

Other: DNA methylation analysis
Correlative studies

Other: gene expression analysis
Correlative studies

Other: bone marrow aspiration
Correlative studies

Other: immunohistochemistry staining method
Correlative studies
Other Name: immunohistochemistry

Other: reverse transcriptase-polymerase chain reaction
Correlative studies
Other Name: RT-PCR

Other: flow cytometry
Correlative studies




Primary Outcome Measures :
  1. Phase I: Highest Tolerated Low Dose (HTLD) [ Time Frame: During the first 28-day cycle ]
    Azacitidine given at low but increasing doses up to 50mg/m2 twice a week. Maximum tolerated dose reported.


Secondary Outcome Measures :
  1. Percent of Participants With Clinical Benefit and Response According to International Response Criteria [ Time Frame: at 6 months ]
    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.

  2. Percent of Participants With Clinical Benefit and Response According to International Response Criteria [ Time Frame: at 12 months ]
    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.

  3. Median Progression-free Survival (PFS) [ Time Frame: Up to 3 years ]
    Median PFS, measured in months from study entry to progression as defined by international response criteria or death of any cause, whichever comes first

  4. Overall Survival [ Time Frame: up to 3 years ]
    Overall survival will be measured from study entry to death from any cause - median months survival will be reported


Other Outcome Measures:
  1. Changes in Global Gene Expression [ Time Frame: before and after the first cycle of therapy ]
    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.

  2. Quantify the Activity of Azacitidine Inactivating Enzyme Cytidine Deaminase (CDA) [ Time Frame: at 6 months ]
    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.

  3. Promoter Demethylation and Gene Reactivation [ Time Frame: within 7 days before treatment start and at the end of cycle #1 ]
    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

  4. CD34+ Cell Yield and Time to Neutrophil and Platelet Recovery [ Time Frame: after cycle 1 (28 days) ]
    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)



Information from the National Library of Medicine

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01155583


Locations
Layout table for location information
United States, Ohio
University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44106
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44195
Sponsors and Collaborators
Case Comprehensive Cancer Center
Investigators
Layout table for investigator information
Principal Investigator: Frederic Reu Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Principal Investigator: Ehsan Malek, MD University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
  Study Documents (Full-Text)

Documents provided by Case Comprehensive Cancer Center:
Informed Consent Form  [PDF] February 17, 2016

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Responsible Party: Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01155583    
Other Study ID Numbers: CASE1A09
NCI-2010-01139 ( Other Identifier: NCI/CTRP )
First Posted: July 2, 2010    Key Record Dates
Results First Posted: October 12, 2020
Last Update Posted: November 16, 2020
Last Verified: October 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Lenalidomide
Azacitidine
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
Immunologic Factors
Angiogenesis Inhibitors