Clinical Trials /

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

NCT00843882

Description:

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.

Related Conditions:
  • Myelodysplastic Syndromes
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Lenalidomide With or Without Epoetin Alfa in Treating Patients With Myelodysplastic Syndrome and Anemia
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2009-01173
  • SECONDARY ID: NCI-2009-01173
  • SECONDARY ID: CDR0000634119
  • SECONDARY ID: E2905
  • SECONDARY ID: ECOG-E2905
  • SECONDARY ID: 09-0095
  • SECONDARY ID: E2905
  • SECONDARY ID: E2905
  • SECONDARY ID: U10CA180820
  • SECONDARY ID: U10CA021115
  • SECONDARY ID: U24CA196172
  • NCT ID: NCT00843882

Conditions

  • Anemia
  • Chronic Myelomonocytic Leukemia
  • de Novo Myelodysplastic Syndrome
  • Myelodysplastic Syndrome
  • Previously Treated Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
Epoetin AlfaEPO, Epogen, Eprex, Procrit, RetacritArm B (lenalidomide, epoetin alfa)
LenalidomideCC-5013, CC5013, CDC 501, RevlimidArm A (lenalidomide)

Purpose

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

      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-/intermediate-1 (Int-1)-risk myelodysplastic syndrome (MDS) patients or erythropoietin
      treatment naïve 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 [CR] + partial
      response [PR]).

      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 CD71^Hi 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: 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 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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (lenalidomide)Active ComparatorPatients receive lenalidomide PO QD on days 1-21.
  • Lenalidomide
Arm B (lenalidomide, epoetin alfa)ExperimentalPatients receive lenalidomide PO QD on days 1-21 and epoetin alfa SC once weekly.
  • Epoetin Alfa
  • Lenalidomide

Eligibility Criteria

        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

          -  Within 56 days prior to randomization: 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

          -  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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Major erythroid response (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
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Time to MER
Time Frame:From randomization to the documented date of MER, assessed up to 16 weeks
Safety Issue:
Description: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.
Measure: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
Time Frame:8 weeks
Safety Issue:
Description:Summarized by Kaplan-Meier method for patients who achieve MER by treatment arms.
Measure:Rate of MER
Time Frame:Up to 6 months
Safety Issue:
Description: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.
Measure:Minor erythroid response rate
Time Frame:8 weeks
Safety Issue:
Description:Compared between treatment arms by Fisher's exact test.
Measure:Cytogenetic response rate
Time Frame:Up to 6 months
Safety Issue:
Description:Calculated by treatment arm among patients with cytogenetic abnormalities, along with its 90% confidence interval.
Measure:Bone marrow response (complete response and partial response) rate
Time Frame:Up to 6 months
Safety Issue:
Description:90% confidence Interval will be calculated by treatment arm.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

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