Lenalidomide Safety/Efficacy in Myelodysplastic Syndromes (MDS) Associated With a Deletion (Del)(5q) Cytogenetic Abnormality

Study Overview
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Brief Summary
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This study is a multicenter, single-arm, open-label study of oral lenalidomide monotherapy administered to red blood cell (RBC) transfusion-dependent subjects with low- or intermediate-1-risk Myelodysplastic Syndromes (MDS) associated with a del (5q31-33) cytogenetic abnormality. Screening procedures will take place within 28 days of the first day of lenalidomide treatment. Subjects will receive lenalidomide in 28-day cycles for up to 6 cycles, or until bone marrow disease progression or progression/relapse following erythroid hematologic improvement is documented. Study visits will occur every cycle (every 28 days) and laboratory monitoring to assess hematological parameters will occur every 14 days. Safety and efficacy assessments to be performed during the study are outlined in the Schedule of Study Assessments.

Official Title
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A Multicenter, Single-arm, Open-label Study of the Efficacy and Safety of Lenalidomide Monotherapy in Red Blood Cell Transfusion-dependent Subjects With Myelodysplastic Syndromes Associated With a Del(5q) Cytogenetic Abnormality.

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: lenalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must understand and voluntarily sign an informed consent form Age 18 years or older at the time of signing the informed consent Must be able to adhere to the study visit schedule and other protocol requirements. Diagnosis of low or intermediate-1-risk International Prognostic Scoring System (IPSS) Myelodysplastic Syndromes (MDS) without an abnormality of chromosome 5 involving a deletion between bands q31 and q33. Red blood cell (RBC) transfusion-dependent anemia defined as having received greater than or equal to 2 units of RBCs within 8 weeks of the first day of study drug treatment. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2. Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy test within 7 days of starting study drug. Sexually active WCBP must agree to use adequate contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) while on study drug. WCBP must agree to have pregnancy tests every 4 weeks while on study drug. Exclusion Criteria: Pregnant or lactating females Prior therapy with lenalidomide. An abnormality of chromosome 5 involving a deletion between bands q31 and q33. Lab Abnormality: Absolute neutrophil count (ANC) <500 cell/mm^3 (0.5*10^9/L) Lab Abnormality: Platelet count <50,000/mm^3 (50*10^9/L) Lab Abnormality: Serum creatinine >2.5 mg/dL (221 mmol/L) Lab Abnormality: Serum total bilirubin >2.0 mg/dL (34 mmol/L) Prior greater than or equal to grade 3 National Cancer Institute (NCI) Common Toxicity Criteria (CTC) allergic reaction/hypersensitivity to thalidomide. Clinically significant anemia due to factors such as iron, B12 or folate deficiencies, autoimmune or hereditary hemolysis or gastrointestinal bleeding If a marrow aspirate is not evaluable for storage iron, transferrin saturation must be > 20% and serum ferritin not less than 50 ng/mL Use of hematopoietic growth factors within 7 days of the first day of study drug treatment. Prior greater than or equal to grade 3 NCI CTC rash or any desquamation (blistering) while taking thalidomide. Chronic use (>2 weeks) of greater than physiologic doses of a corticosteroid agent (dose equivalent to >10 mg/day of prednisone) within 28 days of the first day of study drug treatment. Use of experimental or standard drugs (i.e. chemotherapeutic, immunosuppressive, and cytoprotective agents) for the treatment of MDS within 28 days of the first day of study drug treatment. Prior history of malignancy other than MDS (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for greater than or equal to 3 years. Use of any other experimental therapy within 28 days of the first day of study drug 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lenalidomide<br> | Drug: lenalidomide<br>* 10 mg orally once daily for 21 days out of a 28-day cycle (syncopated); subsequently amended (Amendment 1, dated 27 August 2003) to employ a continuous dosage regimen in which 10 mg was taken once daily for 28 day cycles (continuous). Subjects who initially began a syncopated regimen and who did not experience a dose-limiting adverse event were allowed to switch to the continuous regimen.<br>* Other names: CC-5013;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants Who Achieved Red Blood Cell (RBC) -Transfusion Independence | Number of participants who achieved RBC-transfusion independence, which was defined as the absence of an intravenous infusion of any RBC transfusion during any consecutive rolling 56 days during the treatment period (eg, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc), and accompanied by at least a 1 g/dL increase from screening/baseline in hemoglobin. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Adverse Experiences | Counts of study participants who had adverse events (AEs) during the study. A participant with multiple occurrences of an adverse event within a category is counted only once in that category. Adverse events were evaluated by the investigator. The National Cancer Institute (NCI)'s Common Toxicity Criteria for AEs (NCI CTC) was used to grade AE severity. Severity grade 3= severe and undesirable AE. Severity grade 4= life-threatening or disabling AE. | Up to 2 Years | 
| Participants With a >= 50% Decrease From Baseline in Red Blood Cell (RBC) Transfusion Requirements Over Any Consecutive 56 Days During Study | A participant was categorized as having a transfusion reduction response if there was a ≥ 50% decrease from pretreatment transfusion requirements (before the start of the study mediation) compared to any consecutive 56 days during the study (i.e. post treatment). | Baseline (Day -54 to Day 0), During study (Day 1 up to 2 years) | 
| Time to Transfusion Independence | Transfusion independence was defined as the absence of an intravenous infusion of any RBC transfusion during any consecutive rolling 56 days during the treatment period (e.g., Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.), and accompanied by at least a 1 g/dL increase from screening/baseline in hemoglobin. Time to transfusion independence was defined as the day of the first dose of study drug to the first day of the first 56-day RBC transfusion-free period. | up to 2 years | 
| Participants Who Relapsed or Maintained Their Transfusion Independence After Achieving Transfusion Independence During the Study | Transfusion independence was defined as the absence of an intravenous infusion of any RBC transfusion during any consecutive rolling 56 days during the treatment period (e.g., Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.), and accompanied by at least a 1 g/dL increase from screening/baseline in hemoglobin. Participants who relapsed required a transfusion after the period of transfusion independence. Participants who maintained transfusion independence did not require a transfusion during the remainder of the study. | up to 2 years | 
| Kaplan Meier Estimate for Duration of Transfusion Independence Response | Duration of response is measured from the first of the consecutive 56 days during which the participant was free of RBC transfusions to the date of the first RBC transfusion after this period. Duration of response was censored at the date of last visit for participants who maintained transfusion independence. | up to 2 years | 
| Change in Hemoglobin Concentration From Baseline to Maximum Value During Response Period for Responders | The change from baseline in hemoglobin for participants who became RBC-transfusion independent. The maximum hemoglobin value obtained during the response period is used in the calculation of change from baseline. | Baseline (Day -54 to Day 0), During study (Day 1 up to 2 years) | 
| Participant Counts of Cytogenetic Response | Participants deemed evaluable by the central cytogenetic review had their cytogenetic response categorized as major or minor. A major cytogenetic response was defined as ≥ 20 metaphases recorded at baseline, and at least 1 post baseline evaluation with ≥ 20 metaphases analyzed with no abnormal metaphases observed. A minor cytogenetic response was defined as ≥ 20 metaphases analyzed at baseline, and at least 1 post baseline evaluation with ≥ 20 metaphases analyzed with a ≥ 50% reduction in the proportion of hematopoietic cells with cytogenetic abnormalities compared with baseline. | up to 2 years | 
| Participant Counts of Platelet Response | Major platelet response: participants with a minimum pretreatment platelet of <100,000/mm^3 in all values within 56 days of start of treatment, an absolute increase of ≥30,000/mm^3 sustained for ≥56 consecutive days. In platelet transfusion-dependent participants, a major response was stabilization of platelet counts and platelet transfusion independence. Minor platelet response: participants with a minimum pretreatment platelet of <100,000/mm^3, a ≥ 50% increase in platelet count with a net increase >10,000/mm^3 for a consecutive 56-day period in the absence of platelet transfusions. | up to 2 years | 
| Participant Counts of Absolute Neutrophil Count (ANC) Response | Major neutrophil response: participants with a minimum pretreatment ANC concentration of < 1500/mm^3 in all values obtained within 56 days of start of treatment, a ≥ 100% increase or an absolute increase of ≥ 500/mm^3, whichever was greater (at least to be ≥ 500/mm^3), sustained for 56 consecutive days. Minor neutrophil response: participants with a minimum pretreatment ANC concentration of < 1500/mm^3, an increase in ANC concentration of ≥ 100% sustained for 56 consecutive days. | up to 2 years | 
| Participants With Complete or Partial Bone Marrow Improvement | Bone marrow aspirates were assessed by a central reviewer. A complete bone marrow improvement required a baseline French-American-British (FAB) classification (see Baseline Characteristics) of refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB) or chronic myelomonocytic leukemia (CMML) and a during study assessment of no MDS. A partial bone marrow improvement reflected an improved FAB classification compared to baseline (e.g. RARS to RA) but evidence of MDS continued to exist. | up to 2 years | 
| Participants With Bone Marrow Progression | Bone marrow aspirate was assessed by a central reviewer. Progression is represented in two categories according to changes from baseline in French-American-British (FAB) classification (see Baseline Characteristics): Baseline classification of refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) to a during treatment (plus 30 days) classification of refractory anemia with excess blasts (RAEB). Any baseline FAB classification to a during treatment (plus 30 days) classification of acute myeloid leukemia (AML). | up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDS, CC-5013, Revlimid, Celgene