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

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: NCT00843882
Recruitment Status : Active, not recruiting
First Posted : February 13, 2009
Last Update Posted : June 23, 2020
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE February 12, 2009
First Posted Date  ICMJE February 13, 2009
Last Update Posted Date June 23, 2020
Actual Study Start Date  ICMJE January 29, 2009
Actual Primary Completion Date July 8, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 11, 2019)
Major erythroid response (MER) [ Time Frame: At 16 weeks ]
Will be 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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 12, 2009)
Major erythroid response (MER) at 16 weeks
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 11, 2019)
  • Time to MER [ Time Frame: From randomization to the documented date of MER, assessed up to 16 weeks ]
    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 [ Time Frame: 8 weeks ]
    Will be 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. Summarized by Kaplan-Meier method for patients who achieve MER by treatment arms.
  • Rate of MER [ Time Frame: Up to 6 months ]
    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 ]
    Compared between treatment arms by Fisher's exact test.
  • Cytogenetic response rate [ Time Frame: Up to 6 months ]
    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 ]
    90% confidence Interval will be calculated by treatment arm.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 12, 2009)
  • Time to MER
  • Duration of MER
  • Rate of MER to salvage combination therapy
  • Minor erythroid response rate
  • Cytogenetic response rate
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Lenalidomide With or Without Epoetin Alfa in Treating Patients With Myelodysplastic Syndrome and Anemia
Official Title  ICMJE 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
Brief Summary 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 cells. 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.
Detailed Description


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-/intermediate-1 (Int-1)-risk myelodysplastic syndrome (MDS) patients or erythropoietin treatment naïve patients with low probability of erythropoietin benefit.


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 [CR] + partial response [PR]).

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

VIIIa. Pretreatment and on study endogenous erythropoietin level (Arm A). VIIIb. To evaluate the effect of CD45 isoform profile on lenalidomide enhancement of erythropoietin-induced STAT5 phosphorylation in CD71^Hi erythroid precursors and the relationship to erythroid response.

VIIIc. To characterize molecular targets relevant to lenalidomide cytotoxicity in del5q31.1 cells.

VIIId. 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: Patients are randomized to 1 of 2 treatment arms. Patients with del 5q31.1 karyotype are assigned to Arm A.

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

ARM B: 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 cycles. Patients who achieve a major erythroid response (MER) may continue treatment beyond 4 cycles in the absence of disease progression, disease conversion to acute myeloid leukemia, or unacceptable toxicity. Patients in Arm A 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 B.

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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Anemia
  • Chronic Myelomonocytic Leukemia
  • de Novo Myelodysplastic Syndrome
  • Myelodysplastic Syndrome
Intervention  ICMJE
  • Biological: Epoetin Alfa
    Given SC
    Other Names:
    • EPO
    • Epoetin alfa-epbx
    • Epogen
    • Eprex
    • Procrit
    • Retacrit
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Lenalidomide
    Given PO
    Other Names:
    • CC-5013
    • CC5013
    • CDC 501
    • Revlimid
Study Arms  ICMJE
  • Active Comparator: Arm A (lenalidomide)
    Patients receive lenalidomide PO QD on days 1-21.
    • Other: Laboratory Biomarker Analysis
    • Drug: Lenalidomide
  • Experimental: Arm B (lenalidomide, epoetin alfa)
    Patients receive lenalidomide PO QD on days 1-21 and epoetin alfa SC once weekly.
    • Biological: Epoetin Alfa
    • Other: Laboratory Biomarker Analysis
    • Drug: Lenalidomide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: December 11, 2019)
Original Estimated Enrollment  ICMJE
 (submitted: February 12, 2009)
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date July 8, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • NOTE: Results of the bone marrow biopsy and aspirate as well as cytogenetics are mandatory to register subjects onto study, which are indispensable to determine International Prognostic Scoring System (IPSS) category needed for eligibility; please note that it is not necessary to wait for the week 16, week 32, or week bone marrow and cytogenetic results prior to starting the next cycle unless deemed necessary by the treating physician; one example of this exception can include if the subject shows signs of progression, such as increased peripheral blood blast percentage; at that juncture, the treating physician may prefer to await the results prior to starting a new cycle; if a cycle is started, and based on the bone marrow results it is felt by the treating physician that the subject should not continue on treatment, please be sure to note this information on the case report forms at end of treatment
  • Patient must have documented diagnosis of MDS lasting at least three months (MDS duration >= 3 months) according to World Health Organization (WHO) criteria or non-proliferative chronic myelomonocytic leukemia (CMML) (white blood cell [WBC] < 12,000/mcL)
  • Patient must have IPSS categories of low- or intermediate-1-risk disease; patients must have IPSS score determined by cytogenetic analysis prior to randomization; patients must have cytogenetic analysis done (to calculate IPSS); if the current bone marrow biopsy is a dry tap, patients with cytogenetic failure and < 10% marrow blasts will be eligible; subjects with cytogenetic failure must have previous 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

    • NOTE: For non-transfusion dependent patients (i.e., receiving < 2 units/4 weeks x 8 weeks pre-study) who receive periodic transfusions, the mean 8 week pre-transfusion hemoglobin should be used to determine protocol eligibility and response reference
    • For non-transfusion dependent patients, a minimum of 2 pre-transfusion or un-transfused hemoglobin values are required
  • Applies only for patients without the deletion 5q 31.1; patients must have failed treatment with an erythropoietic growth factor, or have a low probability of response to rhu-erythropoietin; patients with low probability of response to rhu-erythropoietin or prior erythropoietin failures are defined as follows:

    • Prior erythropoietin failure-requires a minimum trial of >= 40,000 units epoetin alfa/week x 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 a >= 2 g rise in hemoglobin sustained for >= 4 weeks in non-transfusion dependent patients
    • Low erythropoietin response profile-rhu-erythropoietin and epoetin alfa-naïve patients receiving >= 2U packed (p)RBC/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
  • Patients must not have documented iron deficiency; all patients must have documented marrow iron stores; if marrow iron stain is not available, the transferrin saturation must be > 20% or a serum ferritin > 100 ng/mL
  • Women must not be 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 discontinuation of lenalidomide therapy; females of 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 seizure 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 (50 x 10^9/L) without platelet transfusion (within 56 days prior to randomization)
  • Absolute neutrophil count (ANC) >= 500 cells/mcL (0.5 x 10^9/L); hence ANC must be >= 500/mcL without myeloid growth factor support (within 56 days prior to randomization)
  • Serum creatinine =< 1.5 times upper limit of normal (ULN) (within 56 days prior to randomization)
  • Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) or serum glutamate pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) =< 2.0 x ULN (within 56 days prior to randomization)
  • Serum total bilirubin < 3.0 mg/dL (within 56 days prior to randomization)
  • Prior thalidomide is 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
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 NCT00843882
Other Study ID Numbers  ICMJE NCI-2009-01173
NCI-2009-01173 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
E2905 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
E2905 ( Other Identifier: CTEP )
U10CA180820 ( U.S. NIH Grant/Contract )
U10CA021115 ( U.S. NIH Grant/Contract )
U24CA196172 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Alan F List ECOG-ACRIN Cancer Research Group
PRS Account National Cancer Institute (NCI)
Verification Date June 2020

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