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

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.

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.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes
• Intervention / Treatment: Drug: lenalidomide

• Study Type: Interventional
• Enrollment (Actual): 148
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Duisburg, Germany
    • St. Johannes Hospital
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic
    • Scottsdale, Arizona, United States, 85258
      • Arizona Cancer Center
    • Tucson, Arizona, United States, 85724-5024
      • Arizona Cancer Center
  • California
    • Rancho Mirage, California, United States, 92270
      • Desert Hematology & Oncology Medical Group
    • Stanford, California, United States, 94305-5750
      • Stanford University Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
    • Lecanto, Florida, United States, 34461
      • Cancer & Blood Disease Center
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comp Cancer Center
    • Tampa, Florida, United States, 33612-9497
      • H. Lee Moffitt Cancer Center and Research Institute
  • Georgia
    • Marietta, Georgia, United States, 30060
      • Northwest Georgia Oncology - Wellstar Cancer Research
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Medical Center
    • Chicago, Illinois, United States, 60612
      • Rush-Presbyterian- St. Luke's Medical Center
    • Skokie, Illinois, United States, 60077
      • Midwest Cancer Research Group
  • Maryland
    • Baltimore, Maryland, United States, 21287-8963
      • Johns Hopkins Oncology Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115-6084
      • Dana-Farber Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48201-2097
      • Wayne State University School of Medicine
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Nebraska
    • Omaha, Nebraska, United States, 68198-7680
      • University of Nebraska Medical Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10029
      • Mt. Sinai Medical Center
    • New York, New York, United States, 10021-6007
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10021-0034
      • New York Hospital-Cornell
    • Rochester, New York, United States, 14642
      • University of Rochester- James P. Wilmot Cancer Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157-1082
      • Wake Forest University School of Medicine
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
  • Oregon
    • Portland, Oregon, United States, 97227
      • Kaiser Permanente Northwest Region
    • Portland, Oregon, United States, 97201
      • Oregon Health & Science University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Western Pennsylvania Cancer Institute
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Cancer Institute
    • Seattle, Washington, United States, 98109-4417
      • Fred Hutchinson Cancer Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Lenalidomide

Drug: lenalidomide; 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.; Other Names: CC-5013

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Celgene
• Investigators: Principal Investigator: Alan F List, MD, H. Lee Moffitt Cancer Center and Research Institute

Publications and helpful links

General Publications

• Sekeres MA, Maciejewski JP, Giagounidis AA, Wride K, Knight R, Raza A, List AF. Relationship of treatment-related cytopenias and response to lenalidomide in patients with lower-risk myelodysplastic syndromes. J Clin Oncol. 2008 Dec 20;26(36):5943-9. doi: 10.1200/JCO.2007.15.5770. Epub 2008 Nov 17.
• Prebet T, Cluzeau T, Park S, Sekeres MA, Germing U, Ades L, Platzbecker U, Gotze K, Vey N, Oliva E, Sugrue MM, Bally C, Kelaidi C, Al Ali N, Fenaux P, Gore SD, Komrokji R. Outcome of patients treated for myelodysplastic syndromes with 5q deletion after failure of lenalidomide therapy. Oncotarget. 2017 Jun 14;8(47):81926-81935. doi: 10.18632/oncotarget.18477. eCollection 2017 Oct 10.
• List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R, Reeder C, Wride K, Patin J, Schmidt M, Zeldis J, Knight R; Myelodysplastic Syndrome-003 Study Investigators. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006 Oct 5;355(14):1456-65. doi: 10.1056/NEJMoa061292.
• A.F. List, et.al. Results of the MDS-002 and -003 international phase II studies evaluating lenalidomide (CC-5013; Revlimid) in the treatment of transfusion-dependent (TD) patients with myelodysplastic syndrome (MDS). European Hematology Association 10th Conference June 2-5, 2005 Abstract #0772
• Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mittelman M, Muus P, Nimer SD, Hellstrom-Lindberg E, Powell BL, Guerci-Bresler A, Sekeres MA, Deeg HJ, Del Canizo C, Greenberg PL, Shammo JM, Skikne B, Yu X, List AF. Clinical characteristics and outcomes according to age in lenalidomide-treated patients with RBC transfusion-dependent lower-risk MDS and del(5q). J Hematol Oncol. 2017 Jun 26;10(1):131. doi: 10.1186/s13045-017-0491-2.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2003
• Primary Completion (Actual): August 1, 2008
• Study Completion (Actual): August 1, 2008

Study Registration Dates

• First Submitted: July 17, 2003
• First Submitted That Met QC Criteria: July 17, 2003
• First Posted (Estimate): July 18, 2003

Study Record Updates

• Last Update Posted (Actual): November 19, 2019
• Last Update Submitted That Met QC Criteria: November 6, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: MDS; Revlimid; CC-5013; Celgene
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Congenital Abnormalities; Bone Marrow Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Chromosome Disorders; Chromosome Aberrations; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Lenalidomide
• Other Study ID Numbers: CC-5013-MDS-003