Overview

This trial is active, not recruiting.

Condition refractory multiple myeloma
Treatments azacitidine, lenalidomide, dexamethasone, dna methylation analysis, gene expression analysis, bone marrow aspiration, immunohistochemistry staining method, reverse transcriptase-polymerase chain reaction, flow cytometry
Phase phase 1/phase 2
Sponsor Case Comprehensive Cancer Center
Collaborator National Cancer Institute (NCI)
Start date June 2010
End date May 2016
Trial size 44 participants
Trial identifier NCT01155583, CASE1A09, NCI-2010-01139

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Endpoint classification safety study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
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.
azacitidine 5-AC
Given SC
lenalidomide CC-5013
Given orally
dexamethasone Aeroseb-Dex
Given orally
dna methylation analysis
Correlative studies
gene expression analysis
Correlative studies
bone marrow aspiration
Correlative studies
immunohistochemistry staining method immunohistochemistry
Correlative studies
reverse transcriptase-polymerase chain reaction RT-PCR
Correlative studies
flow cytometry
Correlative studies

Primary Outcomes

Measure
Phase I: Highest tolerated low dose (HTLD)
time frame: during the first 28-day cycle
Phase II: Response rate as evidence of progressive or new bone lesions
time frame: after 6 months (cycles) of treatment
Phase II: Response rate as evidence of progressive or new bone lesions
time frame: after 12 months (cycles) of treatment

Secondary Outcomes

Measure
Progression-free survival
time frame: followed up every 3 months for 3 years.
Overall survival
time frame: followed up every 3 months for 3 years.
CD34+ cell yield and time to neutrophil and platelet recovery
time frame: after cycle 1 (28 days)
Promoter demethylation and gene reactivation
time frame: within 7 days before treatment start and at the end of cycle #1
Changes in global gene expression
time frame: before and after the first cycle of therapy
Quantify the activity of azacitidine inactivating enzyme cytidine deaminase (CDA)
time frame: at 6 months

Eligibility Criteria

Male or female participants at least 18 years old.

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).

Additional Information

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
Principal investigator Frederic Reu
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.
Trial information was received from ClinicalTrials.gov and was last updated in February 2016.
Information provided to ClinicalTrials.gov by Case Comprehensive Cancer Center.
Location data was received from the National Cancer Institute and was last updated in June 2016.