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

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ClinicalTrials.gov Identifier: NCT00790842
Recruitment Status : Terminated (Slow enrollment)
First Posted : November 14, 2008
Results First Posted : October 24, 2018
Last Update Posted : October 24, 2018
Sponsor:
Collaborator:
Celgene
Information provided by (Responsible Party):
PrECOG, LLC.

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.


Condition or disease Intervention/treatment Phase
Multiple Myeloma Plasma Cell Neoplasm Drug: Lenalidomide Drug: Dexamethasone Drug: Anticoagulants Phase 1 Phase 2

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 : Interventional  (Clinical Trial)
Actual Enrollment : 63 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of the Tolerability of Lenalidomide and Low Dose Dexamethasone in Previously Treated Multiple Myeloma Patients With Impaired Renal Function
Actual Study Start Date : January 21, 2009
Actual Primary Completion Date : September 30, 2017
Actual Study Completion Date : March 8, 2018


Arm Intervention/treatment
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
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

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
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

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
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




Primary Outcome Measures :
  1. 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

  2. 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


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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).

  6. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00790842


Locations
United States, Arizona
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85259-5499
United States, Georgia
Emory University Winship Cancer
Atlanta, Georgia, United States, 30322
United States, Illinois
University of IL at Chicago
Chicago, Illinois, United States, 60612
United States, Iowa
McFarland Clinic
Ames, Iowa, United States, 50010
Siouxland Hematology Oncology Associates
Sioux City, Iowa, United States, 51101
United States, Michigan
Michigan Cancer Research Consortium and Oncology Research- St. Joseph Mercy Hospital - Ann Arbor
Ann Arbor, Michigan, United States, 48106-0955
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Metro MN CCOP
Saint Louis Park, Minnesota, United States, 55416
United States, Nebraska
Missouri Valley Cancer Consortium
Omaha, Nebraska, United States, 68106
United States, North Carolina
Kinston Medical Specialists
Kinston, North Carolina, United States, 28501
United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104-4283
Reading Hospital and Medical Center
West Reading, Pennsylvania, United States, 19611
United States, West Virginia
WVU Mary Babb Randolph Cancer Center
Morgantown, West Virginia, United States, 26506
United States, Wisconsin
Gundersen Lutheran
La Crosse, Wisconsin, United States, 54601
Waukesha Memorial Hospital (ProHealth Care)
Waukesha, Wisconsin, United States, 53188
Aurora Cancer Center
Wauwatosa, Wisconsin, United States, 53226
Sponsors and Collaborators
PrECOG, LLC.
Celgene
Investigators
Study Chair: Joseph R. Mikhael, MD Mayo Clinic
  Study Documents (Full-Text)

Documents provided by PrECOG, LLC.:
Study Protocol  [PDF] March 28, 2011
Statistical Analysis Plan  [PDF] January 26, 2017


Publications of Results:
Responsible Party: PrECOG, LLC.
ClinicalTrials.gov Identifier: NCT00790842     History of Changes
Other Study ID Numbers: PrE1003
RV-MM-PrECOG-0394 ( Other Identifier: Celgene Protocol )
First Posted: November 14, 2008    Key Record Dates
Results First Posted: October 24, 2018
Last Update Posted: October 24, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Data is proprietary.

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by PrECOG, LLC.:
Refractory Multiple Myeloma
Relapsed Multiple Myeloma
Multiple Myeloma with Renal Dysfunction
Stage I Multiple Myeloma
Stage II Multiple Myeloma
Stage III Multiple Myeloma

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Plasmacytoma
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Aspirin
Lenalidomide
Thalidomide
BB 1101
Heparin
Calcium heparin
Heparin, Low-Molecular-Weight
Dalteparin
Anticoagulants
Warfarin
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents