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

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

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.

Study Overview

• Status: Completed
• Conditions: Refractory Multiple Myeloma
• Intervention / Treatment: Other: flow cytometry; Drug: dexamethasone; Other: immunohistochemistry staining method; Drug: lenalidomide; Drug: azacitidine; Other: DNA methylation analysis; Other: gene expression analysis; Other: bone marrow aspiration; Other: reverse transcriptase-polymerase chain reaction

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.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / 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.	Other: flow cytometry; Correlative studies; Drug: dexamethasone; Given orally; Other Names: Aeroseb-Dex; Decaderm; Decadron; DM; DXM; Decaspray; Other: immunohistochemistry staining method; Correlative studies; Other Names: immunohistochemistry; Drug: lenalidomide; Given orally; Other Names: CC-5013; IMiD-1; Revlimid; Drug: azacitidine; Given by subcutaneous injection (SC); Other Names: 5-AC; 5-AZC; Vidaza; 5-azacytidine; azacytidine; ladakamycin; Other: DNA methylation analysis; Correlative studies; Other: gene expression analysis; Correlative studies; Other: bone marrow aspiration; Correlative studies; Other: reverse transcriptase-polymerase chain reaction; Correlative studies; Other Names: RT-PCR
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.	Other: flow cytometry; Correlative studies; Drug: dexamethasone; Given orally; Other Names: Aeroseb-Dex; Decaderm; Decadron; DM; DXM; Decaspray; Other: immunohistochemistry staining method; Correlative studies; Other Names: immunohistochemistry; Drug: lenalidomide; Given orally; Other Names: CC-5013; IMiD-1; Revlimid; Drug: azacitidine; Given by subcutaneous injection (SC); Other Names: 5-AC; 5-AZC; Vidaza; 5-azacytidine; azacytidine; ladakamycin; Other: DNA methylation analysis; Correlative studies; Other: gene expression analysis; Correlative studies; Other: bone marrow aspiration; Correlative studies; Other: reverse transcriptase-polymerase chain reaction; Correlative studies; Other Names: RT-PCR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	During the first 28-day cycle

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	at 6 months
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.	at 12 months
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	Up to 3 years
Overall Survival	Overall survival will be measured from study entry to death from any cause - median months survival will be reported	up to 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Global Gene Expression	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.	before and after the first cycle of therapy
Quantify the Activity of Azacitidine Inactivating Enzyme Cytidine Deaminase (CDA)	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.	at 6 months
Promoter Demethylation and Gene Reactivation	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	within 7 days before treatment start and at the end of cycle #1
CD34+ Cell Yield and Time to Neutrophil and Platelet Recovery	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)	after cycle 1 (28 days)

Collaborators and Investigators

• Sponsor: Case Comprehensive Cancer Center
• Investigators: Principal Investigator: Frederic Reu, Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (ACTUAL): May 28, 2016
• Study Completion (ACTUAL): November 6, 2018

Study Registration Dates

• First Submitted: June 30, 2010
• First Submitted That Met QC Criteria: July 1, 2010
• First Posted (ESTIMATE): July 2, 2010

Study Record Updates

• Last Update Posted (ACTUAL): November 16, 2020
• Last Update Submitted That Met QC Criteria: October 20, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dexamethasone; Lenalidomide; Azacitidine
• Other Study ID Numbers: CASE1A09; NCI-2010-01139 (OTHER: NCI/CTRP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No