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

Study Overview
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Brief Summary
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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
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PRIMARY OBJECTIVE: 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 relation 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. Patients undergo bone marrow biopsy at screening and during follow-up. Patients undergo blood specimen collection on study. ARM B: Patients receive lenalidomide PO QD on days 1-21 and epoetin alfa subcutaneously (SC) once weekly. Patients undergo bone marrow biopsy at screening and during follow-up. Patients undergo blood specimen collection on study. 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.

Official Title
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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

Conditions
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Anemia, Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndrome, Myelodysplastic Syndrome

Intervention / Treatment
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* Procedure: Bone Marrow Biopsy
* Biological: Epoetin Alfa
* Other: Laboratory Biomarker Analysis
* Drug: Lenalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years 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 International Prognostic Scoring System (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 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 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) Inclusion criteria 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 Exclusion Criteria: 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) 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 Prior thalidomide therapy 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 Exclusion criteria for crossover registration from Arm A (lenalidomide alone) to Arm B (lenalidomide and epoetin alfa): Patients must not have a limiting unresolved grade 3 or greater toxicity from lenalidomide monotherapy or drug intolerance preventing continuation of lenalidomide treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (lenalidomide)<br>Patients receive lenalidomide PO QD on days 1-21. Patients undergo bone marrow biopsy at screening and during follow-up. Patients undergo blood specimen collection on study. | Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;|
| Experimental: Arm B (lenalidomide, epoetin alfa)<br>Patients receive lenalidomide PO QD on days 1-21 and epoetin alfa SC once weekly. Patients undergo bone marrow biopsy at screening and during follow-up. Patients undergo blood specimen collection on study. | Procedure: Bone Marrow Biopsy<br>* Undergo bone marrow biopsy<br>* Other names: Biopsy, Bone Marrow;Biological: Epoetin Alfa<br>* Given SC<br>* Other names: Retacrit;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Major Erythroid Response (MER) | Major erythroid response is defined as transfusion-independence for ≥ 8 consecutive weeks for patients who were red blood cell transfusion-dependent at baseline AND a ≥ 1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value; or a > 2 g/dL rise in hemoglobin without transfusion for non-transfusion dependent patients. | Assessed after completion of 16 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Major Erythroid Response (MER) | Time to major erythroid response (MER) is defined in responders as the time from randomization to the documented date of MER. For transfusion independent patients, the date of MER is the first date of the elevation in hemoglobin level of more than 2 g/dL that has been sustained for at least 8 weeks. For transfusion dependent patients, the date of MER is the beginning date of the time interval of transfusion independence that has been sustained for at least eight weeks. | Assessed every cycle during treatment and then 3 and 6 months after last protocol treatment | 
| Duration of Major Erythroid Response (MER) | Duration of major erythroid response (MER) is defined as the time interval between the documented date of MER and the earliest date of resumption of red blood cell transfusions ≥ 2 units in an 8-week period, a reduction in hemoglobin concentration ≥ 2 g/dL in the absence of acute infection, gastrointestinal bleeding and hemolysis, or death. | Assessed every cycle during treatment and then 3 and 6 months after last protocol treatment | 
| Proportion of Patients With Major Erythroid Response (MER) to Salvage Combination Therapy | Major erythroid response is defined as transfusion-independence for ≥ 8 consecutive weeks for patients who were red blood cell transfusion-dependent at baseline AND a ≥ 1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value; or a > 2 g/dL rise in hemoglobin without transfusion for non-transfusion dependent patients. | Assessed after completion of 16 weeks of treatment | 
| Proportion of Patients With Minor Erythroid Response | The definition of minor erythroid response: the mean hemoglobin is sustained 1.0 to 2.0 g/dL above the baseline value for a minimum of 8 weeks; or a 50% or greater decrease in 8-week red blood cell transfusion requirements compared to baseline. | Assessed every cycle during treatment and after completion of 16 weeks of treatment | 
| Proportion of Patients With Major Erythroid Response (MER) Among Those With Chromosome 5q31.1 Deletion | Major erythroid response is defined as transfusion-independence for ≥ 8 consecutive weeks for patients who were red blood cell transfusion-dependent at baseline AND a ≥ 1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value; or a > 2 g/dL rise in hemoglobin without transfusion for non-transfusion dependent patients. | Assessed after completion of 16 weeks of treatment | 
| Proportion of Patients With Bone Marrow Response | Bone marrow response includes complete remission (CR) and partial remission (PR). Complete remission (CR): Bone marrow showing < 5% myeloblasts with normal maturation of all cell lines, with no evidence for dysplasia. When erythroid precursors constitute < 50% of bone marrow nucleated cells, the percent of blasts is based on all nucleated cells; when there are ≥ 50% erythroid cells, the percent blasts should be based on the non-erythroid cells. Partial remission (PR): All of the CR criteria (if abnormal prior to treatment), except blasts decreased by 50% over pre-treatment, or a less advanced Myelodysplastic Syndromes (MDS) World Health Organization (WHO) classification than pretreatment. Cellularity and morphology are not relevant. | Assessed at 16 weeks | 
| Proportion of Patients With Cytogenetic Response | Evaluation of cytogenetic response requires 20 analyzable metaphases when using conventional techniques. Analysis of data will require 20 metaphases before and after treatment, which must be done on bone marrow only (peripheral blood is not a substitute). Fluorescent in situ hybridization (FISH) may be used as a supplement to follow a specifically defined cytogenetic abnormality, but it is not a substitute for conventional cytogenetic studies. Cytogenetic response is defined as follows: Complete response: Restoration of a normal karyotype in patients with a documented pre-existing clonal (>2 metaphases abnormal) chromosome abnormalities. Partial response: > 50% reduction in the percentage of bone marrow metaphases with only clonal abnormality. | Assessed at baseline and after completion of 16 weeks of treatment | 
| Association Between Major Erythroid Response and Cytogenetic Response | Major erythroid response is defined as transfusion-independence for ≥ 8 consecutive weeks for patients who were red blood cell transfusion-dependent at baseline AND a ≥ 1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value; or a > 2 g/dL rise in hemoglobin without transfusion for non-transfusion dependent patients. Evaluation of cytogenetic response requires 20 analyzable metaphases before and after treatment, which must be done on bone marrow only. Fluorescent in situ hybridization (FISH) may be used as a supplement to follow a specifically defined cytogenetic abnormality, but it is not a substitute for conventional cytogenetic studies. Cytogenetic response is defined as follows: Complete response: Restoration of a normal karyotype in patients with a documented pre-existing clonal (>2 metaphases abnormal) chromosome abnormalities. Partial response: > 50% reduction in the percentage of bone marrow metaphases with only clonal abnormality. | Assessed at baseline and after completion of 16 weeks of treatment | 
| Pretreatment Endogenous Erythropoietin Level | Pretreatment endogenous erythropoietin level was assessed at baseline. The association between pretreatment endogenous erythropoietin level and major erythroid response was evaluated among patients who received lenalidomide alone. Major erythroid response is defined as transfusion-independence for ≥ 8 consecutive weeks for patients who were red blood cell transfusion-dependent at baseline AND a ≥ 1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value; or a > 2 g/dL rise in hemoglobin without transfusion for non-transfusion dependent patients. | Assessed at baseline and after completion of 16 weeks of treatment |