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

Primary Purpose

Multiple Myeloma, Plasma Cell Neoplasm

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Lenalidomide
Dexamethasone
Anticoagulants
Sponsored by
PrECOG, LLC.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multiple Myeloma focused on measuring Refractory Multiple Myeloma, Relapsed Multiple Myeloma, Multiple Myeloma with Renal Dysfunction, Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Mayo Clinic in Arizona
  • Emory University Winship Cancer
  • University of IL at Chicago
  • McFarland Clinic
  • Siouxland Hematology Oncology Associates
  • Michigan Cancer Research Consortium and Oncology Research- St. Joseph Mercy Hospital - Ann Arbor
  • Mayo Clinic
  • Metro MN CCOP
  • Missouri Valley Cancer Consortium
  • Kinston Medical Specialists
  • University of Pennsylvania
  • Reading Hospital and Medical Center
  • WVU Mary Babb Randolph Cancer Center
  • Gundersen Lutheran
  • Waukesha Memorial Hospital (ProHealth Care)
  • Aurora Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Group A - CrCl 30-60 mL/min

Group B, CrCl < 30 mL/min

Group C, CrCl < 30 mL/min, on dialysis

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

Number of Participants in Phase I Component With Dose Limiting Toxicities During the First Cycle of Therapy
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]
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

Overall Survival Time
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
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
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
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
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
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.

Full Information

First Posted
November 13, 2008
Last Updated
September 22, 2018
Sponsor
PrECOG, LLC.
Collaborators
Celgene
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1. Study Identification

Unique Protocol Identification Number
NCT00790842
Brief Title
Lenalidomide and Low-Dose Dexamethasone in Patients With Previously Treated Multiple Myeloma and Kidney Dysfunction
Acronym
PrE1003
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2018
Overall Recruitment Status
Terminated
Why Stopped
Slow enrollment
Study Start Date
January 21, 2009 (Actual)
Primary Completion Date
September 30, 2017 (Actual)
Study Completion Date
March 8, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
PrECOG, LLC.
Collaborators
Celgene

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Myeloma, Plasma Cell Neoplasm
Keywords
Refractory Multiple Myeloma, Relapsed Multiple Myeloma, Multiple Myeloma with Renal Dysfunction, Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
63 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group A - CrCl 30-60 mL/min
Arm Type
Experimental
Arm Description
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.
Arm Title
Group B, CrCl < 30 mL/min
Arm Type
Experimental
Arm Description
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.
Arm Title
Group C, CrCl < 30 mL/min, on dialysis
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Lenalidomide
Other Intervention Name(s)
Revlimid
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Other Intervention Name(s)
Decadron
Intervention Description
40 mg given by mouth days 1, 8, 15 and 22 of a 28-day cycle. Continue until disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Anticoagulants
Other Intervention Name(s)
Aspirin, Heparin, Low Molecular Weight Heparin, Coumadin
Intervention Description
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.
Primary Outcome Measure Information:
Title
Number of Participants in Phase I Component With Dose Limiting Toxicities During the First Cycle of Therapy
Description
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
Time Frame
First cycle of therapy (28 days)
Title
Percentage of Participants Who Experience a Response [sCR, CR, VGPR, PR]
Description
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
Time Frame
56 months
Secondary Outcome Measure Information:
Title
Overall Survival Time
Description
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.
Time Frame
56 months
Title
Duration of Response
Description
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.
Time Frame
56 months
Title
Worst Degree Treatment-Related Adverse Events Across All Event Types Per Patient
Description
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.
Time Frame
56 months
Title
Renal Function Over Time
Description
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.
Time Frame
56 months
Title
Pharmacokinetics of Lenalidomide in Impaired Renal Function
Description
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).
Time Frame
56 months
Title
Progression-free Survival
Description
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.
Time Frame
56 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joseph R. Mikhael, MD
Organizational Affiliation
Mayo Clinic
Official's Role
Study Chair
Facility Information:
Facility Name
Mayo Clinic in Arizona
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259-5499
Country
United States
Facility Name
Emory University Winship Cancer
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
University of IL at Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
McFarland Clinic
City
Ames
State/Province
Iowa
ZIP/Postal Code
50010
Country
United States
Facility Name
Siouxland Hematology Oncology Associates
City
Sioux City
State/Province
Iowa
ZIP/Postal Code
51101
Country
United States
Facility Name
Michigan Cancer Research Consortium and Oncology Research- St. Joseph Mercy Hospital - Ann Arbor
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48106-0955
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Metro MN CCOP
City
Saint Louis Park
State/Province
Minnesota
ZIP/Postal Code
55416
Country
United States
Facility Name
Missouri Valley Cancer Consortium
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68106
Country
United States
Facility Name
Kinston Medical Specialists
City
Kinston
State/Province
North Carolina
ZIP/Postal Code
28501
Country
United States
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104-4283
Country
United States
Facility Name
Reading Hospital and Medical Center
City
West Reading
State/Province
Pennsylvania
ZIP/Postal Code
19611
Country
United States
Facility Name
WVU Mary Babb Randolph Cancer Center
City
Morgantown
State/Province
West Virginia
ZIP/Postal Code
26506
Country
United States
Facility Name
Gundersen Lutheran
City
La Crosse
State/Province
Wisconsin
ZIP/Postal Code
54601
Country
United States
Facility Name
Waukesha Memorial Hospital (ProHealth Care)
City
Waukesha
State/Province
Wisconsin
ZIP/Postal Code
53188
Country
United States
Facility Name
Aurora Cancer Center
City
Wauwatosa
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Data is proprietary.
Citations:
PubMed Identifier
30190454
Citation
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.
Results Reference
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Lenalidomide and Low-Dose Dexamethasone in Patients With Previously Treated Multiple Myeloma and Kidney Dysfunction

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