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Lenalidomide and Low-Dose Dexamethasone in Patients With Previously Treated Multiple Myeloma and Kidney Dysfunction (PrE1003)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00790842
Recruitment Status : Terminated (Slow enrollment)
First Posted : November 14, 2008
Results First Posted : October 24, 2018
Last Update Posted : October 24, 2018
Information provided by (Responsible Party):

Tracking Information
First Submitted Date  ICMJE November 13, 2008
First Posted Date  ICMJE November 14, 2008
Results First Submitted Date  ICMJE July 29, 2018
Results First Posted Date  ICMJE October 24, 2018
Last Update Posted Date October 24, 2018
Actual Study Start Date  ICMJE January 21, 2009
Actual Primary Completion Date September 30, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 22, 2018)
  • Number of Participants in Phase I Component With Dose Limiting Toxicities During the First Cycle of Therapy [ Time Frame: First cycle of therapy (28 days) ]
    Dose Limiting Toxicity (DLT) was defined as any of the following events determined by the investigator to be possibly, probably, or definitely related to lenalidomide within the first cycle of therapy irrespective of whether the adverse events resolved:
    • Grade 3 or higher neutropenia with fever ≥38.5 degrees C
    • Grade 4 neutropenia ≥7 days
    • Grade 4 or higher thrombocytopenia
    • Other non-hematologic Grade 4 or higher adverse event not present prior to starting therapy or not due to underlying cause
  • Percentage of Participants Who Experience a Response [sCR, CR, VGPR, PR] [ Time Frame: 56 months ]
    Per International Myeloma Working Group criteria, complete response (CR): negative immunofixation of serum and urine, normalization of free light chain (FLC) ratio if at study entry FLC was only measurable non-bone parameter, <5% plasma cells in bone marrow, disappearance of any soft tissue plasma cytomas; stringent complete response (sCR): all of above, + normal serum FLC ratio in all patients and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence; partial response (PR): >=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to < 200 mg per 24 hours, >=50% decrease in difference between involved and uninvolved FLC levels or a 50% decrease in level of involved FLC with 50% decrease in ratio, >=50% reduction in bone marrow plasma cells, if baseline percentage was >=30%, >=50% reduction in size of soft tissue plasmacytoma; very good partial response (VGPR): PR + improvements in serum and urine M-components
Original Primary Outcome Measures  ICMJE
 (submitted: November 13, 2008)
  • Maximum tolerated dose of lenalidomide (Phase I)
  • Toxicity profile as assessed by NCI CTCAE v3.0 (Phase I)
  • Time to any treatment-related toxicity, treatment-related grade 3+ toxicity, and hematologic nadirs (WBC, ANC, and platelet counts) (Phase I)
  • Time to progression and time to treatment failure (Phase I)
  • Proportion of patients with at least partial response (Phase II)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 22, 2018)
  • Overall Survival Time [ Time Frame: 56 months ]
    Overall survival is the time from registration to death from any cause. Patients alive at the time of analysis were censored at the date last known alive.
  • Duration of Response [ Time Frame: 56 months ]
    Duration of response was defined as time between the onset of response and disease progression in months, among patients treated at the recommended phase II dose who experienced a response to treatment. Per criteria of the International Myeloma Working Group, progressive disease was defined as one of the following: increase of 25% from best confirmed response in serum M-component, urine M-component, free light chain (FLC), bone marrow plasma cell percentage, or development of new or increase in size of bone lesions or soft tissue plasma cytomas. Development of hypercalcemia that can be attributed solely to the myeloma also constituted progression.
  • Worst Degree Treatment-Related Adverse Events Across All Event Types Per Patient [ Time Frame: 56 months ]
    The highest degree of any adverse event experienced by each patient, as assessed by NCI CTCAE Version 4, with an attribution of possibly, probably, or definitely related to treatment. Reportable adverse events included those occurring while on treatment or within 30 days of the end of treatment.
  • Renal Function Over Time [ Time Frame: 56 months ]
    To describe renal function over time and to evaluate the safety profile of a onetime increase in lenalidomide dose at least 2 cycles after start of treatment due to improved renal function.
  • Pharmacokinetics of Lenalidomide in Impaired Renal Function [ Time Frame: 56 months ]
    To determine the pharmacokinetics of lenalidomide administration in myeloma patients with impaired renal function (pharmacokinetic analysis will be performed in up to 12 consented Mayo Clinic subjects treated during the Phase II component of the trial (only).
  • Progression-free Survival [ Time Frame: 56 months ]
    Progression-free survival is the time from registration to disease progression or death. Patients alive without disease progression were censored at the time of the last disease assessment.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 13, 2008)
  • Survival time (Phase II)
  • Progression-free survival time (Phase II)
  • Duration of response (Phase II)
  • Time to treatment failure (Phase II)
  • Adverse events (Phase II)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Lenalidomide and Low-Dose Dexamethasone in Patients With Previously Treated Multiple Myeloma and Kidney Dysfunction
Official Title  ICMJE A Phase I/II Study of the Tolerability of Lenalidomide and Low Dose Dexamethasone in Previously Treated Multiple Myeloma Patients With Impaired Renal Function
Brief Summary

Patients with previously treated multiple myeloma and kidney dysfunction will be treated with lenalidomide and low-dose dexamethasone. Phase I will study the side effects and best dose of lenalidomide when given together with low-dose dexamethasone therapy. After the maximum safe and tolerated dose is found in Phase I, the study will proceed to Phase II. Phase II will study how well the the treatment works in patients with previously treated (relapsed or refractory) multiple myeloma and kidney dysfunction.

Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving lenalidomide together with dexamethasone may kill more cancer cells. Lenalidomide and dexamethasone may have different effects in patients who have changes in their kidney function.

Detailed Description

Multiple Myeloma (MM) affects approximately 20,000 Americans annually and remains an incurable hematologic malignancy characterized by frequent early response followed by universal treatment relapse necessitating multiple sequential therapeutic regimens. Until recently, few effective therapies existed. Several novel agents for MM have now become available including the immunomodulatory drugs thalidomide, lenalidomide, as well as the proteasome inhibitor, bortezomib. Each of these agents is undergoing extensive clinical evaluation in combination with other therapies to produce unprecedented response rates in newly diagnosed and relapsed MM. Lenalidomide has proven to be a highly effective treatment agent, particularly when used in combination with dexamethasone but is renally excreted and little information is available about its use in myeloma patients with impaired kidney function (20% have renal failure at some time after diagnosis). Defining a safe and effective dose of lenalidomide to use is a critical step in MM treatment.

OUTLINE: This is a Phase I, dose-escalation study of lenalidomide followed by a Phase II study. Patients are stratified according to degree of renal dysfunction (moderate [creatinine clearance 30-60 mL/min] vs severe [creatinine clearance <30 mL/min and does not require dialysis] vs end-stage renal disease [creatinine clearance <30 mL/min and requires dialysis]).

Patients receive oral lenalidomide on days 1-21 and low-dose oral dexamethasone 40 mg on days 1, 8, 15, and 22. There is a 7 day rest (days 22-28) from lenalidomide. Each cycle is 28 days and repeated in the absence of disease progression or unacceptable toxicity.

Patients enrolled in the phase II portion of the study will undergo blood sample collection periodically for pharmacokinetic analysis of lenalidomide (Mayo Clinic sites only).

After completion of study treatment, patients are followed every 6 months for up to 3 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Multiple Myeloma
  • Plasma Cell Neoplasm
Intervention  ICMJE
  • Drug: Lenalidomide
    Given by mouth days 1-21 of a 28-day cycle. There is a 7 day rest (days 22-28). Continue until disease progression or unacceptable toxicity.
    Other Name: Revlimid
  • Drug: Dexamethasone
    40 mg given by mouth days 1, 8, 15 and 22 of a 28-day cycle. Continue until disease progression or unacceptable toxicity.
    Other Name: Decadron
  • Drug: Anticoagulants
    Anticoagulation consisted of aspirin at either 81 mg/day or 325 mg/day at the physician's discretion. Heparin, low molecular weight heparin, or coumadin could be used if the patient was intolerant to aspirin.
    Other Names:
    • Aspirin
    • Heparin
    • Low Molecular Weight Heparin
    • Coumadin
Study Arms  ICMJE
  • Experimental: Group A - CrCl 30-60 mL/min
    Creatinine clearance 30 - 60 mL/min, lenalidomide dose determined in phase I, dexamethasone 40 mg orally days 1, 8, 15 and 22 of a 28 day cycle, and anticoagulants.
    • Drug: Lenalidomide
    • Drug: Dexamethasone
    • Drug: Anticoagulants
  • Experimental: Group B, CrCl < 30 mL/min
    Creatinine clearance < 30 mL/min, not on dialysis, lenalidomide dose determined in phase I, dexamethasone 40 mg orally days 1, 8, 15 and 22 of a 28 day cycle, and anticoagulants.
    • Drug: Lenalidomide
    • Drug: Dexamethasone
    • Drug: Anticoagulants
  • Experimental: Group C, CrCl < 30 mL/min, on dialysis
    Creatinine clearance < 30 mL/min and on dialysis, lenalidomide dose determined in phase I, dexamethasone 40 mg orally days 1, 8, 15 and 22 of a 28 day cycle, and anticoagulants.
    • Drug: Lenalidomide
    • Drug: Dexamethasone
    • Drug: Anticoagulants
Publications * Mikhael J, Manola J, Dueck AC, Hayman S, Oettel K, Kanate AS, Lonial S, Rajkumar SV. Lenalidomide and dexamethasone in patients with relapsed multiple myeloma and impaired renal function: PrE1003, a PrECOG study. Blood Cancer J. 2018 Aug 29;8(9):86. doi: 10.1038/s41408-018-0110-7.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: September 22, 2018)
Original Estimated Enrollment  ICMJE
 (submitted: November 13, 2008)
Actual Study Completion Date  ICMJE March 8, 2018
Actual Primary Completion Date September 30, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosed with previously treated multiple myeloma.
  • Measurable disease assessed by one of the following ≤21 days prior to registration:

    • Serum monoclonal protein ≥1 g by protein electrophoresis
    • Urine monoclonal protein >200 mg on 24 hour electrophoresis
    • Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa to lambda free light chain ratio
    • Monoclonal bone marrow plasmacytosis ≥30% (evaluable disease)
    • If both serum and urine m-components are present, both must be followed in order to evaluate response.
  • All previous cancer therapy including chemotherapy, radiation, hormonal therapy and surgery, must be discontinued ≥2 weeks prior to registration.
  • Age ≥18 years.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
  • Acceptable organ and marrow function ≤21 days prior to registration:

    • Absolute neutrophil count (ANC) ≥1000/mm³
    • Platelet count ≥75,000/mm³
    • Total bilirubin ≤2 mg/dL
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x upper limit of normal
  • Renal impairment at baseline as measured by serum creatinine clearance (CrCl) ≤60 mL/min ≤21 days prior to registration.
  • Females of Childbearing Potential (FCBP) must have a negative pregnancy test within 10-14 days and again within 24 hours of starting Cycle 1 and must use an effective double-method contraception for ≥28 days prior to, during, and for ≥28 days after completion of study therapy.
  • Able to take required prophylactic anticoagulation.
  • Able to understand and willingness to sign a written informed consent.
  • Willing to provide blood samples for research purposes (Mayo Clinic sites only).
  • If previously received lenalidomide, demonstration of clinical response of any duration or stable disease with progression-free interval of ≥6 months from start of that therapy.

Exclusion Criteria:

  • Concurrent use of other anti-cancer agents or treatments. Growth factors and bisphosphonates are allowed as medically indicated. Steroids may be used with an equivalency of up to 20 mg of Prednisone per day as long as the dose has not been adjusted upwards in past 2 weeks prior to study registration.
  • Uncontrolled intercurrent illness including, but not limited to, any of the following:

    • Ongoing or active infection requiring IV antibiotics
    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Uncontrolled cardiac arrhythmia
    • Psychiatric illness/social situation that would limit compliance with study requirements.
  • Any of the following as this regimen may be harmful to a developing fetus or nursing child:

    • Pregnant women
    • Breast-feeding women
    • Men or women of childbearing potential or their sexual partners who are unwilling to employ adequate contraception.
  • HIV-positive patients on combination antiretroviral therapy.
  • Known hypersensitivity to thalidomide or other immunomodulatory drugs.
  • History of Stevens-Johnson syndrome characterized by a desquamating rash while taking thalidomide or similar drugs.
  • Other active malignancy except for non melanoma skin cancer or in situ cervical or breast cancer.
  • Concurrent radiation therapy, except for palliation of a single painful bone lesion or fracture.
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 NCT00790842
Other Study ID Numbers  ICMJE PrE1003
RV-MM-PrECOG-0394 ( Other Identifier: Celgene Protocol )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Data is proprietary.
Responsible Party PrECOG, LLC.
Study Sponsor  ICMJE PrECOG, LLC.
Collaborators  ICMJE Celgene
Investigators  ICMJE
Study Chair: Joseph R. Mikhael, MD Mayo Clinic
PRS Account PrECOG, LLC.
Verification Date September 2018

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