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

Purpose

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	Intervention	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


Study Type:	Interventional
Study Design:	Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: 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

Resource links provided by NLM:

Genetics Home Reference related topics: multiple myeloma

MedlinePlus related topics: Genes and Gene Therapy Multiple Myeloma

Drug Information available for: Dexamethasone Azacitidine Dexamethasone sodium phosphate Dexamethasone acetate Lenalidomide

Genetic and Rare Diseases Information Center resources: Multiple Myeloma

U.S. FDA Resources

Further study details as provided by Case Comprehensive Cancer Center:

Primary Outcome Measures:

Phase I: Highest tolerated low dose (HTLD) [ Time Frame: during the first 28-day cycle ] [ Designated as safety issue: Yes ]
azacitidine given at low but increasing doses up to 50mg/m2 twice a week
Phase II: Response rate as evidence of progressive or new bone lesions [ Time Frame: after 6 months (cycles) of treatment ] [ Designated as safety issue: No ]
Response according to international response criteria (>= PR) and 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.
Phase II: Response rate as evidence of progressive or new bone lesions [ Time Frame: after 12 months (cycles) of treatment ] [ Designated as safety issue: No ]
Response according to international response criteria (>= PR) and 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.

Secondary Outcome Measures:

Progression-free survival [ Time Frame: followed up every 3 months for 3 years. ] [ Designated as safety issue: No ]
Overall survival [ Time Frame: followed up every 3 months for 3 years. ] [ Designated as safety issue: No ]
CD34+ cell yield and time to neutrophil and platelet recovery [ Time Frame: after cycle 1 (28 days) ] [ Designated as safety issue: No ]
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)
Promoter demethylation and gene reactivation [ Time Frame: within 7 days before treatment start and at the end of cycle #1 ] [ Designated as safety issue: No ]
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
Changes in global gene expression [ Time Frame: before and after the first cycle of therapy ] [ Designated as safety issue: No ]
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.
Quantify the activity of azacitidine inactivating enzyme cytidine deaminase (CDA) [ Time Frame: at 6 months ] [ Designated as safety issue: No ]
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.


Enrollment:	45
Study Start Date:	June 2010
Estimated Primary Completion Date:	May 2017 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Arm I 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.	Drug: azacitidine Given 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

Arms

Assigned Interventions

Experimental: Arm I

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.

Drug: azacitidine

Given 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

Detailed Description:

PRIMARY OBJECTIVES:

Phase I: 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 standard dose lenalidomide and low dose dexamethasone in patients with relapsed or refractory multiple myeloma.

Phase II: Response according to international response criteria (>= PR) and clinical benefit response (>= minor response according to adapted EBMT (European Group for Blood and Marrow Transplantation) criteria). PR=partial response

SECONDARY OBJECTIVES:

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 level after cycle 1
Changes in global gene expression in myeloma cells treated at the HTLD 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.

Eligibility


Ages Eligible for Study:	18 Years and older (Adult, Senior)
Genders Eligible for Study:	Both
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.
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 (Cockroft-Gault) ≥ 30ml/min.
- Total bilirubin ≤ 1.5 x 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 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 Cockroft-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).

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01155583

Locations


United States, Ohio
Case Medical Center, 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

National Cancer Institute (NCI)

Investigators


Principal Investigator:	Frederic Reu	Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Principal Investigator:	Ehsan Malek, MD	Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

More Information


Responsible Party:	Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier:	NCT01155583 History of Changes
Other Study ID Numbers:	CASE1A09 NCI-2010-01139 CASE1A09
Study First Received:	June 30, 2010
Last Updated:	May 9, 2016
Health Authority:	United States: Institutional Review Board United States: Food and Drug Administration

Additional relevant 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 acetate	Dexamethasone Dexamethasone 21-phosphate Lenalidomide Thalidomide Azacitidine BB 1101 Anti-Inflammatory Agents Antiemetics Autonomic Agents Peripheral Nervous System Agents Physiological Effects of Drugs Gastrointestinal Agents Glucocorticoids Hormones Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on September 28, 2016