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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Refractory Multiple Myeloma

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A - Azacitidine/Lenalidomide/Dexamethasone<br>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<br>* Given by subcutaneous injection (SC)<br>* Other names: Vidaza;Drug: lenalidomide<br>* Given orally<br>* Other names: Revlimid;Drug: dexamethasone<br>* Given orally<br>* Other names: DXM;Other: DNA methylation analysis<br>* Correlative studies<br>Other: gene expression analysis<br>* Correlative studies<br>Other: bone marrow aspiration<br>* Correlative studies<br>Other: immunohistochemistry staining method<br>* Correlative studies<br>* Other names: immunohistochemistry;Other: reverse transcriptase-polymerase chain reaction<br>* Correlative studies<br>* Other names: RT-PCR;Other: flow cytometry<br>* Correlative studies<br>|
| Experimental: Arm B - Chronic Kidney Disease (CDK) Cohort<br>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<br>* Given by subcutaneous injection (SC)<br>* Other names: Vidaza;Drug: lenalidomide<br>* Given orally<br>* Other names: Revlimid;Drug: dexamethasone<br>* Given orally<br>* Other names: DXM;Other: DNA methylation analysis<br>* Correlative studies<br>Other: gene expression analysis<br>* Correlative studies<br>Other: bone marrow aspiration<br>* Correlative studies<br>Other: immunohistochemistry staining method<br>* Correlative studies<br>* Other names: immunohistochemistry;Other: reverse transcriptase-polymerase chain reaction<br>* Correlative studies<br>* Other names: RT-PCR;Other: flow cytometry<br>* Correlative studies<br>|

What is the study measuring?
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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 |