Clinical trial NCT00790842: Lenalidomide and Low-Dose Dexamethasone in Patients With Previously Treated Multiple Myeloma and Kidney Dysfunction
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
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: 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
Lead sponsor: PrECOG, LLC.
Sponsor class: OTHER
Collaborators: name: Celgene
First posted: 2008-11-14
Enrollment: 63
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Number of Participants in Phase I Component With Dose Limiting Toxicities During the First Cycle of Therapy
timeFrame: First cycle of therapy (28 days)
measure: Percentage of Participants Who Experience a Response [sCR, CR, VGPR, PR]
timeFrame: 56 months
Secondary outcomes:
measure: Overall Survival Time
timeFrame: 56 months
measure: Duration of Response
timeFrame: 56 months
measure: Worst Degree Treatment-Related Adverse Events Across All Event Types Per Patient
timeFrame: 56 months
measure: Renal Function Over Time
timeFrame: 56 months
measure: Pharmacokinetics of Lenalidomide in Impaired Renal Function
timeFrame: 56 months
measure: Progression-free Survival
timeFrame: 56 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic in Arizona
state: Arizona
city: Atlanta
country: United States
facility: Emory University Winship Cancer
state: Georgia
city: Chicago
country: United States
facility: University of IL at Chicago
state: Illinois
city: Ames
country: United States
facility: McFarland Clinic
state: Iowa
city: Sioux City
country: United States
facility: Siouxland Hematology Oncology Associates
state: Iowa
city: Ann Arbor
country: United States
facility: Michigan Cancer Research Consortium and Oncology Research- St. Joseph Mercy Hospital - Ann Arbor
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis Park
country: United States
facility: Metro MN CCOP
state: Minnesota
city: Omaha
country: United States
facility: Missouri Valley Cancer Consortium
state: Nebraska
city: Kinston
country: United States
facility: Kinston Medical Specialists
state: North Carolina
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: West Reading
country: United States
facility: Reading Hospital and Medical Center
state: Pennsylvania
city: Morgantown
country: United States
facility: WVU Mary Babb Randolph Cancer Center
state: West Virginia
city: La Crosse
country: United States
facility: Gundersen Lutheran
state: Wisconsin
city: Waukesha
country: United States
facility: Waukesha Memorial Hospital (ProHealth Care)
state: Wisconsin
city: Wauwatosa
country: United States
facility: Aurora Cancer Center
state: Wisconsin
Study officials:
affiliation: Mayo Clinic
name: Joseph R. Mikhael, MD
role: STUDY_CHAIR
References:
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.