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Bendamustine Hydrochloride, Lenalidomide, and Dexamethasone in Treating Patients With Relapsed Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT01049945
Recruitment Status : Completed
First Posted : January 15, 2010
Results First Posted : March 30, 2015
Last Update Posted : February 11, 2020
Sponsor:
Information provided by (Responsible Party):
Mayo Clinic

Tracking Information
First Submitted Date  ICMJE January 14, 2010
First Posted Date  ICMJE January 15, 2010
Results First Submitted Date  ICMJE March 23, 2015
Results First Posted Date  ICMJE March 30, 2015
Last Update Posted Date February 11, 2020
Actual Study Start Date  ICMJE February 2010
Actual Primary Completion Date November 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 28, 2016)
  • Dose Limiting Toxicity of Bendamustine Hydrochloride and Lenalidomide in Combination With Dexamethasone (Phase I) [ Time Frame: One cycle of treatment ]
    The Maximum Tolerated Dose (MTD) is the dose level below that at which a dose limiting toxicity (DLT) is observed in ≥ 33% (i.e., ≥ 2 of 6) subjects in a cohort. A dose limiting toxicity is defined as one of the following adverse events in the Common Terminology Criteria for Adverse Events (CTCAE) v 3.0 deemed at least possibly related to treatment:
    • Grade 2 neuropathy with pain
    • Any grade 3 Non-Hematologic toxicity
    • Any grade Non-Hematologic event requiring a dose reduction in cycle 1 or delaying the next cycle by >14 days.
    • Grade 4 neutropenia
    • Febrile neutropenia
    • Grade 4 thrombocytopenia
    • Grade 3 thrombocytopenia associated with bleeding
    • Any Hematologic event requiring a dose reduction in cycle 1 or a delay in the next cycle of treatment by >14 days.
    We are reporting the results of this endpoint as the number of DLTs per dose level.
  • Confirmed Response Rate (Dose Level 4) Reported as the Percentage of Patients Achieving a Confirmed Response (sCR, CR, VGPR, or PR). [ Time Frame: Up to 6 cycles of treatment ]
    Complete response (CR) - Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. Stringent complete response (sCR) - A CR plus normal FLC ratio and no clonal cells in bone marrow Near complete response (nCR) A CR, with the persistence of original monoclonal protein Very good partial response (VGPR) - Serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-component plus urine M-component <100 mg per 24 h Partial response (PR)
    • ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 h.
    • a ≥50% decrease in the difference between involved and uninvolved FLC levels
    • or a ≥50% reduction in plasma cells is required in place of M-protein, if ≥30% at baseline.
Original Primary Outcome Measures  ICMJE
 (submitted: January 14, 2010)
  • Maximum Tolerated Dose of Bendamustine Hydrochloride and Lenalidomide in Combination With Dexamethasone (Phase I)
  • Confirmed response rate (phase II)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 10, 2020)
  • Duration of Response (DOR) (Phase II) [ Time Frame: Up to 2 years from study completion ]
    DOR is the time from the date the patient's objective status is first noted to be PR or better to the earliest date of progression (PD=Increase of > 25% from lowest response value in Serum/Urine M-component) is documented. Treatment response was assessed using the International Myeloma Working Group uniform criteria. Complete response (CR)=Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. Stringent complete response (sCR)=A CR plus normal FLC ratio and no clonal cells in bone marrow. Near complete response (nCR)=A CR, with the persistence of original monoclonal protein. Very good partial response (VGPR) =Serum and urine M-component detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-component plus urine M-component <100 mg per 24 h, Partial response (PR)=≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 h.
  • Event Free Survival (Phase II) [ Time Frame: Up to 2 years from study completion ]
    The event-free survival time is defined as the time from registration to disease progression (PD=Increase of > 25% from lowest response value in Serum/Urine M-component) while receiving bendamustine, lenalidomide, and dexamethasone, death due to any cause, or subsequent treatment for multiple myeloma. The distribution of event-free survival will be estimated using the method of Kaplan-Meier. Treatment response was assessed using the International Myeloma Working Group uniform criteria.
  • Progression Free Survival (Phase II) [ Time Frame: Up to 2 years from study completion ]
    The progression-free survival time is defined as the time from registration to disease progression (PD=Increase of > 25% from lowest response value in Serum/Urine M-component) while receiving bendamustine, lenalidomide, and dexamethasone or death due to any cause, whichever comes first. The distribution of progression-free survival will be estimated using the method of Kaplan-Meier. Treatment response was assessed using the International Myeloma Working Group uniform criteria.
  • Overall Survival (Phase II) [ Time Frame: at 6 months ]
    The overall survival time is defined as the time from registration to death due to any cause. The distribution of overall survival will be estimated using the method of Kaplan-Meier. The overall survival rate at 6 months is defined as the percentage of participants who are alive at 6 months.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 14, 2010)
  • Duration of Response (Phase II)
  • Time to Progression (Phase II)
  • Progression Free Survival (Phase II)
  • Overall Survival (Phase II)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Bendamustine Hydrochloride, Lenalidomide, and Dexamethasone in Treating Patients With Relapsed Multiple Myeloma
Official Title  ICMJE A Phase I/II, Multicenter, Open-label, Dose-escalation Study of Bendamustine in Combination With Lenalidomide and Dexamethasone in Patients With Relapsed Multiple Myeloma
Brief Summary RATIONALE: Drugs used in chemotherapy, such as bendamustine hydrochloride and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Giving bendamustine hydrochloride 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 bendamustine hydrochloride and lenalidomide when given together with dexamethasone and to see how well they work in treating patients with relapsed multiple myeloma.
Detailed Description PRIMARY OBJECTIVES: I. To determine the Maximum Tolerated Dose (MTD) of bendamustine and lenalidomide in combination with dexamethasone in subjects with Multiple Myeloma (MM) in first or second relapse. (Phase I) II. To evaluate the confirmed response rate of bendamustine in combination with lenalidomide and dexamethasone in subjects with MM in first or second relapse. (Phase II) SECONDARY OBJECTIVES: I. To evaluate the safety of bendamustine in combination with lenalidomide and dexamethasone. (Phase I and II) II. To evaluate time-to-tumor-progression, progression-free survival, duration of response, and overall survival. (Phase II) OUTLINE: This is a phase I dose escalation study of bendamustine hydrochloride and lenalidomide followed by a phase II study. Patients receive dexamethasone orally or IV on days 1, 8, 15, and 22; bendamustine hydrochloride IV over 30 minutes on days 1 and 2; and oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving at least stable disease after 6 courses may continue to receive lenalidomide and dexamethasone as above in the absence of disease progression or unacceptable toxicity. Dexamethasone may be discontinued after 12 courses of therapy at the treating investigator's discretion. After completion of study treatment, patients are followed at 4 weeks and then periodically for up to 2 years.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Refractory Multiple Myeloma
Intervention  ICMJE
  • Drug: bendamustine hydrochloride
    Given IV
    Other Names:
    • bendamustin hydrochloride
    • bendamustine
    • cytostasan hydrochloride
    • Ribomustin
    • SDX-105
    • Treanda
  • Drug: lenalidomide
    Given orally
    Other Names:
    • CC-5013
    • IMiD-1
    • Revlimid
  • Drug: dexamethasone
    Given orally or IV
    Other Names:
    • Aeroseb-Dex
    • Decaderm
    • Decadron
    • Decaspray
    • DM
    • DXM
Study Arms  ICMJE Experimental: Arm I
Patients receive dexamethasone orally or IV on days 1, 8, 15, and 22; bendamustine hydrochloride IV over 30 minutes on days 1 and 2; and oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: bendamustine hydrochloride
  • Drug: lenalidomide
  • Drug: dexamethasone
Publications * Kumar SK, Krishnan A, LaPlant B, Laumann K, Roy V, Zimmerman T, Gertz MA, Buadi FK, Stockerl Goldstein K, Birgin A, Fiala M, Duarte L, Maharaj M, Levy J, Vij R. Bendamustine, lenalidomide, and dexamethasone (BRD) is highly effective with durable responses in relapsed multiple myeloma. Am J Hematol. 2015 Dec;90(12):1106-10. doi: 10.1002/ajh.24181. Epub 2015 Oct 6.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 23, 2015)
70
Original Estimated Enrollment  ICMJE
 (submitted: January 14, 2010)
84
Actual Study Completion Date  ICMJE September 16, 2015
Actual Primary Completion Date November 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion:

  • Diagnosis of MM and documentation of at least 1 prior therapy (induction therapy followed by stem cell transplantation is considered one prior therapy) but not more than two previous therapies
  • 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 starting lenalidomide
  • Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure
  • Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information
  • Able to take aspirin (325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA or at high risk of developing thrombosis may use warfarin or low molecular weight heparin)
  • AST (SGOT) and ALT (SGPT) =< 3.0 x upper limit of normal (ULN)
  • Creatinine clearance >= 60 mL/min (Cockcroft-Gault calculation) for patients enrolled in Phase 1 and Creatinine clearance >= 30 mL/min (Cockcroft-Gault calculation) for patients enrolled in phase 2 portion
  • Patients with measurable disease, defined by any of the following: serum monoclonal protein >= 1.0 g by protein electrophoresis; > 200 mg of monoclonal protein in the urine on 24-hour electrophoresis; serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio; or monoclonal bone marrow plasmacytosis >= 30% (evaluable disease)
  • All necessary baseline studies for determining eligibility must be obtained within 21 days prior to enrollment
  • Subject has an ECOG =< 2 OR Karnofsky >= 60% performance status; patients with lower performance status based solely on bone pain secondary to multiple myeloma will be eligible
  • FCBP 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
  • Absolute neutrophil count (ANC) >= 1,000 cells/dL (1.0 x 10^9/L) (growth factors cannot be used within 14 days of first drug administration)
  • Untransfused platelet count >= 75,000 cells/dL (50 x 10^9/L) for patients in whom < 50% of bone marrow nucleated cells are plasma cells; but platelet count >=50,000/dL for patients in whom 50% of bone marrow nucleated cells are plasma cells
  • Total Bilirubin =< 1.5 mg/dL
  • Hemoglobin >= 8.0 g/dl

Exclusion:

  • Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy
  • Patients may be receiving concomitant therapy with bisphosphonates and low dose corticosteroids (e.g., prednisone up to but no more than 10 mg p.o. q.d. or its equivalent) for symptom management and comorbid conditions; doses of corticosteroid should be stable for at least 7 days prior to study treatment
  • Prior radiation therapy within 2 weeks of the first dose of study treatment
  • Known active infection requiring parenteral or oral anti-infective treatment
  • Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse follow-up evaluation
  • Patient has hypersensitivity to any of the components of study therapy - Known HIV or active hepatitis B or C viral infection
  • Known hypersensitivity to required prophylactic medications
  • Patient has received other investigational drugs within 14 days before enrollment
  • Pregnant or breast-feeding females (lactating females must agree not to breast feed while taking lenalidomide)
  • Subjects with evidence of mucosal or internal bleeding and/or platelet transfusion refractory (i.e., unable to maintain a platelet count >= 50,000 cells/mm^3)
  • Concurrent therapy with a marketed or investigational anticancer therapy
  • Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient
  • Other investigational agents are not to be used during the study
  • Prior peripheral stem cell transplant within 12 weeks of the first dose of study treatment
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01049945
Other Study ID Numbers  ICMJE MMRC-020-021
NCI-2009-01535 ( Registry Identifier: NCI's CTRO )
MMRC-020-021 ( Other Identifier: Mayo Clinic Cancer Center & MMRC )
09-004211 ( Other Identifier: Mayo Clinic IRB )
C18083/6125 ( Other Identifier: Cephalon protocol )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mayo Clinic
Study Sponsor  ICMJE Mayo Clinic
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Shaji K. Kumar, M.D. Mayo Clinic
Principal Investigator: Vivek Roy, M.D. Mayo Clinic
PRS Account Mayo Clinic
Verification Date April 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP