Lenalidomide With or Without Epoetin Alfa in Treating Patients With Myelodysplastic Syndrome and Anemia

This study is currently recruiting participants.
Verified April 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00843882
First received: February 12, 2009
Last updated: April 9, 2014
Last verified: April 2014

February 12, 2009
April 9, 2014
January 2009
April 2017   (final data collection date for primary outcome measure)
MER defined as sustained transfusion independence in transfusion-dependent patients or a rise in hemoglobin > 2 g/dL in transfusion-independent patients with anemia for a minimum of 8 consecutive weeks [ Time Frame: At 16 weeks ] [ Designated as safety issue: No ]
Major erythroid response (MER) at 16 weeks [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00843882 on ClinicalTrials.gov Archive Site
  • Time to MER [ Time Frame: From randomization to the documented date of MER, assessed up to 16 weeks ] [ Designated as safety issue: No ]
    Time to MER will be compared between lenalidomide monotherapy and combined treatment of lenalidomide and epoetin alfa in MER responders, using a one-sided log-rank test at the significance level of 0.025.
  • Duration of MER defined as the time interval between the documented date of MER and the earliest date of resumption of RBC transfusions > 2 units a reduction in hemoglobin concentration >= 2 g/dL in the absence of acute infection [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Summarized by Kaplan-Meier method for patients who achieve MER by treatment arms.
  • Rate of MER [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]
    The 90% confidence interval of the rate of MER to salvage combination therapy will be computed in patients who fail to achieve an MER with lenalidomide monotherapy and cross over to the combination therapy.
  • Minor erythroid response rate [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Compared between treatment arms by Fisher's exact test.
  • Cytogenetic response rate [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]
    Calculated by treatment arm among patients with cytogenetic abnormalities, along with its 90% confidence interval.
  • Bone marrow response (complete response and partial response) rate [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]
    90% confidence Interval will be calculated by treatment arm.
  • Time to MER [ Designated as safety issue: No ]
  • Duration of MER [ Designated as safety issue: No ]
  • Rate of MER to salvage combination therapy [ Designated as safety issue: No ]
  • Minor erythroid response rate [ Designated as safety issue: No ]
  • Cytogenetic response rate [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Lenalidomide With or Without Epoetin Alfa in Treating Patients With Myelodysplastic Syndrome and Anemia
Randomized Phase III Trial Comparing the Frequency of Major Erythroid Response (MER) to Treatment With Lenalidomide (Revlimid®) Alone and in Combination With Epoetin Alfa (Procrit®) in Subjects With Low- or Intermediate-1 Risk MDS and Symptomatic Anemia

This randomized phase III trial studies lenalidomide to see how well it works with or without epoetin alfa in treating patients with myelodysplastic syndrome and anemia. Lenalidomide may stop the growth of myelodysplastic syndrome by blocking blood flow to the cell. Colony stimulating factors, such as epoetin alfa, may increase the number of immune cells found in bone marrow or peripheral blood. It is not yet known whether lenalidomide is more effective with or without epoetin alfa in treating patients with myelodysplastic syndrome and anemia.

PRIMARY OBJECTIVES:

I. To compare the rate of major erythroid response (MER) between lenalidomide monotherapy and combined treatment of lenalidomide and epoetin alfa in erythropoietin non-responsive low- or intermediate-1-risk myelodysplastic syndrome (MDS) patients or erythropoietin treatment naive patients with low probability of erythropoietin benefit.

SECONDARY OBJECTIVES:

I. To compare the time to MER by treatment assignment. II. To evaluate the duration of MER by treatment assignment. III. To estimate the frequency of MER to salvage combination therapy in patients who fail to experience a MER with lenalidomide monotherapy.

IV. To evaluate and compare the frequency of minor erythroid response by treatment assignment.

V. To investigate the mechanism and target of lenalidomide action in patients with chromosome 5q31.1 deletion.

VI. To evaluate the frequency of cytogenetic response and progression, and the relationship between cytogenetic pattern and erythroid response.

VII. To evaluate the frequency of bone marrow response (complete response and partial response).

VIII. To evaluate the relationship between erythroid response and laboratory correlates outlined below:

  • Pretreatment and on study endogenous erythropoietin level (Arm A).
  • To evaluate the effect of CD45 isoform profile on lenalidomide enhancement of erythropoietin-induced STAT5 phosphorylation in CD71Hi erythroid precursors and the relationship to erythroid response.
  • To characterize molecular targets relevant to lenalidomide cytotoxicity in del5q31.1 cells.
  • To evaluate the frequency of cryptic chromosome 5q31.1 deletions in patients with non-del5q31.1 MDS by array-based genomic scan, and to determine the relationship to hematologic response.

OUTLINE: This is a multicenter study. Patients are stratified according to erythropoietin level (=< 500 mU/mL vs > 500 mU/mL) and prior erythropoietic growth factor (yes vs no). Patients are randomized to 1 of 2 treatment arms. Patients with del 5q31.1 karyotype are assigned to treatment arm I.

ARM I: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21.

ARM II: Patients receive lenalidomide PO QD on days 1-21 and epoetin alfa subcutaneously (SC) once weekly.

In both arms, treatment repeats every 28 days for 4 courses. Patients who achieve a major erythroid response (MER) may continue treatment beyond 4 courses in the absence of disease progression, disease conversion to acute myeloid leukemia, or unacceptable toxicity. Patients in arm I who fail to achieve MER or who achieve MER but relapse after 16 weeks of treatment with lenalidomide may crossover and receive treatment in arm II.

After completion of study treatment, patients are followed for 6 months.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Anemia
  • Chronic Myelomonocytic Leukemia
  • de Novo Myelodysplastic Syndromes
  • Previously Treated Myelodysplastic Syndromes
  • Drug: lenalidomide
    Given PO
    Other Names:
    • CC-5013
    • IMiD-1
    • Revlimid
  • Biological: epoetin alfa
    Given SC
    Other Names:
    • EPO
    • Epogen
    • Eprex
    • erythropoietin
    • Procrit
  • Other: laboratory biomarker analysis
    Correlative studies
  • Active Comparator: Arm I (lenalidomide)
    Patients receive lenalidomide PO QD on days 1-21.
    Interventions:
    • Drug: lenalidomide
    • Other: laboratory biomarker analysis
  • Experimental: Arm II (lenalidomide, epoetin alfa)
    Patients receive lenalidomide PO QD on days 1-21 and epoetin alfa SC once weekly.
    Interventions:
    • Drug: lenalidomide
    • Biological: epoetin alfa
    • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
252
Not Provided
April 2017   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Documented diagnosis of 1 of the following:

    • Myelodysplastic syndromes (MDS) lasting at least 3 months (MDS duration >= 3 months) according to World Health Organization (WHO) criteria or non-proliferative chronic myelomonocytic leukemia (CMML) (white blood cells [WBC] < 12,000/mcL)
  • International prognostic scoring system (IPSS) category of low- or intermediate-1-risk MDS as determined by cytogenetic analysis

    • Cytogenetic analysis required if current bone marrow biopsy is a dry tap
    • Patients with cytogenetic failure and < 10% marrow blasts are eligible

      • Patients with cytogenetic failure must have prior cytogenetic results (fluorescence in situ hybridization [FISH] is not a substitute) within the last 6 months post last type of MDS treatment (in this case, not referring to growth factors as type of MDS treatment)
  • Must have symptomatic anemia untransfused with hemoglobin < 9.5 g/dL =< 8 weeks prior to randomization or with red blood cells (RBC) transfusion dependence (i.e., >= 2 units/month) confirmed for =< 8 weeks before randomization
  • For patients without the deletion 5q 31.1, must have failed treatment with an erythropoietic growth factor OR have a low probability of response to rhu-erythropoietin, as defined by the following:

    • Prior erythropoietin failure: requires >= 40,000 units epoetin alfa/week for 8 weeks or equivalent dose of darbepoetin alfa for 8 weeks with failure to achieve transfusion independence in dependent patients or a failure to achieve >= 2 g rise in hemoglobin sustained for >= 4 weeks in non-transfusion dependent patients
    • Low erythropoietin response profile: rhu-erythropoietin and epoetin alfa-naive patients receiving >= 2 U pRBC/month for a minimum of 8 weeks and serum erythropoietin > 500 mU/mL in the 8 weeks prior to randomization for a hemoglobin < 9.5 g/dL
  • Patients must be off all non-transfusion therapy for MDS for 28 days prior to initiation of study treatment, including all types of growth factors; patients may receive hydrocortisone prophylactically to prevent transfusion reactions
  • Patients must have a serum erythropoietin level documented before randomization and =< 56 days before Day 1 of study treatment; NOTE: hemoglobin must be < 9.5 g/dL at time that serum erythropoietin is drawn
  • No documented iron deficiency

    • Must have documented bone marrow iron stores (if marrow iron stain is not available, transferrin saturation must be > 20% or serum ferritin > 100 ng/mL)
  • Women must not pregnant or breastfeeding; females of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days and again within 24 hours prior to starting Cycle 1 of lenalidomide; a female of childbearing potential(FCBP) is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months; FCBP must also agree to ongoing pregnancy testing
  • Effective contraception must be used by patients participating in lenalidomide therapy, and all patients must agree to counseling by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure; females of childbearing potential (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 starting lenalidomide, during lenalidomide therapy, during dose interruptions, and for at least 28 days following childbearing potential should be referred to a qualified provider of contraceptive methods, if needed; males receiving lenalidomide must agree to use a latex condom during any sexual contact with females of childbearing potential even if they have undergone a successful vasectomy
  • Patients must not have prior therapy with lenalidomide
  • Patients must not have a diagnosis of uncontrolled seizures or uncontrolled hypertension
  • Patients must not have proliferative (WBC >= 12,000/mcL) chronic myelomonocytic leukemia (CMML); WBC must be < 12,000/mcL
  • Patients must not have MDS secondary to treatment with radiotherapy, chemotherapy, and/or immunotherapy for malignant or autoimmune diseases
  • Platelet count >= 50,000/mcL (without platelet transfusion)
  • Absolute neutrophil count (ANC) >= 500 cells/mcL (must be >= 500/mcL without myeloid growth factor support)
  • Serum creatinine =< 1.5 times upper limit of normal (ULN)
  • Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) or serum glutamic pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) =< 2.0 x ULN
  • Serum total bilirubin < 3.0 mg/dL
  • Prior thalidomide allowed, however, patients must not have prior >= grade-3 allergic reactions to thalidomide
  • Patients must not have prior history of desquamating rash from thalidomide at time of study entry
  • Patients must not have clinically significant anemia resulting from iron, B12 or folate deficiencies, autoimmune or hereditary hemolysis, or gastrointestinal bleeding
  • Patients must not have used cytotoxic chemotherapeutic agents or experimental agents (agents that are not commercially available) for the treatment of MDS within 8 weeks of randomization
  • Patients must not have prior history of malignancy other than MDS (except basal cell or squamous skin cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been confirmed free of disease for >= 3 years
  • Patients must not have any serious medical condition or any other unstable medical co-morbidity, or psychiatric illness that will prevent the subject from signing the informed consent form or will place the subject at unacceptable risk if he/she participates in the study
  • Patients must not have a history of thrombo-embolic events within 3 years prior to study randomization
  • Patients must not have known human immunodeficiency virus (HIV)-1 seropositivity because HIV can be an alternate cause of anemia
  • Patients must not have a known allergic reaction to epoetin alfa (Procrit) or human serum albumin
  • Eligibility for crossover registration from Arm A (lenalidomide alone) to Arm B (lenalidomide and epoetin alfa):
  • Patients must have completed 16 weeks of monotherapy with lenalidomide
  • Patients must show failure to achieve MER (major erythroid response) or have achieved MER but relapsed on Arm A
  • Patients must not have a limiting unresolved grade 3 or greater toxicity from lenalidomide monotherapy or drug intolerance preventing continuation of lenalidomide treatment
Both
18 Years and older
No
Not Provided
United States
 
NCT00843882
NCI-2009-01173, NCI-2009-01173, CDR0000634119, U10CA021115, ECOG-E2905, E2905, E2905, U10CA021115
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Alan List Eastern Cooperative Oncology Group
National Cancer Institute (NCI)
April 2014

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