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

NCT01155583 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: CASE1A09NCI-2010-01139
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 2

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.

Conditions

Refractory Multiple Myeloma

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Percent of Participants With Clinical Benefit and Response According to International Response Criteria

  at 6 months

• Percent of Participants With Clinical Benefit and Response According to International Response Criteria

  at 12 months

• Median Progression-free Survival (PFS)

  Up to 3 years

• Overall Survival

  up to 3 years

Other Outcomes (4)

• Changes in Global Gene Expression

  before and after the first cycle of therapy

• Quantify the Activity of Azacitidine Inactivating Enzyme Cytidine Deaminase (CDA)

  at 6 months

• Promoter Demethylation and Gene Reactivation

  within 7 days before treatment start and at the end of cycle #1

Study Arms (2)

Arm A - Azacitidine/Lenalidomide/Dexamethasone

EXPERIMENTAL

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; 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

Arm B - Chronic Kidney Disease (CDK) Cohort

EXPERIMENTAL

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; 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

Interventions

azacitidine DRUG

Given by subcutaneous injection (SC)

Also known as: 5-AC, 5-azacytidine, 5-AZC, azacytidine, ladakamycin, Vidaza

Arm A - Azacitidine/Lenalidomide/Dexamethasone; Arm B - Chronic Kidney Disease (CDK) Cohort

lenalidomide DRUG

Given orally

Also known as: CC-5013, IMiD-1, Revlimid

Arm A - Azacitidine/Lenalidomide/Dexamethasone; Arm B - Chronic Kidney Disease (CDK) Cohort

dexamethasone DRUG

Given orally

Also known as: Aeroseb-Dex, Decaderm, Decadron, Decaspray, DM, DXM

Arm A - Azacitidine/Lenalidomide/Dexamethasone; Arm B - Chronic Kidney Disease (CDK) Cohort

DNA methylation analysis OTHER

Correlative studies

Arm A - Azacitidine/Lenalidomide/Dexamethasone; Arm B - Chronic Kidney Disease (CDK) Cohort

gene expression analysis OTHER

Correlative studies

Arm A - Azacitidine/Lenalidomide/Dexamethasone; Arm B - Chronic Kidney Disease (CDK) Cohort

bone marrow aspiration OTHER

Correlative studies

Arm A - Azacitidine/Lenalidomide/Dexamethasone; Arm B - Chronic Kidney Disease (CDK) Cohort

immunohistochemistry staining method OTHER

Correlative studies

Also known as: immunohistochemistry

Arm A - Azacitidine/Lenalidomide/Dexamethasone; Arm B - Chronic Kidney Disease (CDK) Cohort

reverse transcriptase-polymerase chain reaction OTHER

Correlative studies

Also known as: RT-PCR

Arm A - Azacitidine/Lenalidomide/Dexamethasone; Arm B - Chronic Kidney Disease (CDK) Cohort

flow cytometry OTHER

Correlative studies

Arm A - Azacitidine/Lenalidomide/Dexamethasone; Arm B - Chronic Kidney Disease (CDK) Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Case Comprehensive Cancer Center: lead

Study Sites (2)

University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

Cleveland, Ohio, 44106, United States

Location

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Cleveland, Ohio, 44195, United States

Location

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Azacitidine; Lenalidomide; Dexamethasone; Calcium Dobesilate; DNA Methylation; Gene Expression Profiling; Immunohistochemistry; Reverse Transcriptase Polymerase Chain Reaction; Flow Cytometry

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Piperidones; Piperidines; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Methylation; Alkylation; Biochemical Phenomena; Chemical Phenomena; Metabolism; Genetic Phenomena; Genetic Techniques; Investigative Techniques; Histocytochemistry; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Histological Techniques; Immunologic Techniques; Polymerase Chain Reaction; Nucleic Acid Amplification Techniques; Cell Separation; Cytophotometry; Fluorometry; Luminescent Measurements; Photometry; Chemistry Techniques, Analytical

Results Point of Contact

• Title: Dr. Jason Valent
• Organization: Cleveland Clinic, Case Comprehensive Cancer Center

VALENTJ3@ccf.org

+1 216-445-7238

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 30, 2010
• First Posted: July 2, 2010
• Study Start: June 1, 2010
• Primary Completion: May 28, 2016
• Study Completion: November 6, 2018
• Last Updated: November 16, 2020
• Results First Posted: October 12, 2020

Record last verified: 2020-10

Locations

US (2)