Lenalidomide Versus Placebo in Myelodysplastic Syndromes With a Deletion 5q[31] Abnormality - Full Text View

Purpose

The purpose of this study was to compare 2 doses (10 mg and 5 mg) of lenalidomide to that of placebo in subjects with red blood cell (RBC) transfusion-dependent low- or intermediate-1-risk IPSS MDS associated with a deletion (del) 5q[31] cytogenetic abnormality. Study participants were randomized to one of the two treatment groups or to placebo and took the study drug for 16 weeks. At this timepoint, participants were evaluated for erythroid response. If participants did not achieve at least a minor erythroid response, they were discontinued from the Double-Blind phase and entered into the Open-Label phase. All erythroid responders at Week 16 were to continue in the Double-Blind phase for up to 52 weeks. For participants that were still responding at the end of Double-Blind phase, they could then rollover into the Open-Label phase for an additional two years. Participants could remain on study for up to a total of 3 years. All participants who discontinued from the study were followed every 4 months for overall survival and progression to acute myeloid leukemia (AML).

Condition	Intervention	Phase
Myelodysplastic Syndromes	Drug: Lenalidomide 5 mg Drug: Lenalidomide 10 mg Drug: Placebo	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 3-Arm Study of the Efficacy and Safety of 2 Doses of Lenalidomide Versus Placebo in Red Blood Cell (RBC) Transfusion-Dependent Subjects With Low- or Intermediate-1-Risk Myelodysplastic Syndromes Associated With a Deletion (Del) 5q[31] Cytogenetic Abnormality

Resource links provided by NLM:

Genetics Home Reference related topics: tetrasomy 18p

MedlinePlus related topics: Anemia Blood Transfusion and Donation Leukemia Myelodysplastic Syndromes

Drug Information available for: Lenalidomide

U.S. FDA Resources

Further study details as provided by Celgene Corporation:

Primary Outcome Measures:

Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for >= 26 Weeks (182 Days) [ Time Frame: Up to 52 weeks ] [ Designated as safety issue: No ]
The count of study participants who had no RBC transfusions for 26 consecutive weeks or more during the double-blind period.

Secondary Outcome Measures:

Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for 56 Days [ Time Frame: Up to 52 weeks ] [ Designated as safety issue: No ]
Count of study participants who had no RBC transfusions during any 56 or more consecutive study days during the double-blind period.
Duration of Red Blood Cell (RBC) Transfusion Independence for Participants Who Became RBC Transfusion Independent for at Least 182 Days [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
Mean number of weeks that participants who achieved RBC transfusion independence for at least 182 days were able to maintain RBC transfusion independence. Both double-blind and open-label periods are included.
Maximum Change From Baseline in Hemoglobin During the Double-blind Period for Participants Who Became Red Blood Cell (RBC) Transfusion Independent for at Least 182 Days [ Time Frame: Baseline, up to 52 weeks ] [ Designated as safety issue: No ]
For participants who became RBC transfusion independent for at least 182 days during the double-blind study period, the mean maximum change from baseline in hemoglobin is summarized.
Participants' Response in Platelet Counts as Defined by the International MDS Working Group (IWG 2000) During Double-blind Period [ Time Frame: up to 52 weeks ] [ Designated as safety issue: No ]
The International MDS Working Group (IWG) defines a major platelet response for participants with a pre-treatment platelet count of <100,000/mm^3 as an absolute increase of ≥30,000/mm^3 whereas a minor response is defined as a ≥50% increase in platelet count with a net increase greater than 10,000/mm^3 but less than 30,000/mm^3.
Participants' Response in Absolute Neutrophil Counts as Defined by the International MDS Working Group (IWG 2000) During Double-blind Period [ Time Frame: up to week 52 ] [ Designated as safety issue: No ]
A major neutrophil response is defined by the International MDS Working Group (IWG) criteria as at least a 100% increase, or an absolute increase of ≥500/mm^3 for participants with absolute neutrophil counts (ANC) of less than 1,500/mm^3 before therapy, whichever is greater. A minor response for such participants is defined as an ANC increase of at least 100%, but absolute increase <500/mm^3.
Participants' Response Based on Bone Marrow Samples by the International MDS Working Group (IWG 2000) During Double-blind Period [ Time Frame: up to 52 weeks ] [ Designated as safety issue: No ]
The IWG criteria for bone marrow improvement: a complete remission is bone marrow sampling showing less than 5% myeloblasts with normal maturation of all cell lines, with no evidence for dysplasia. A partial remission is ≥ 50% decrease in blasts over pre-treatment. Bone marrow progression is a ≥ 50% increase in blasts that exceed the top range of the pretreatment percentile range: a) <5% blasts b) 5-10% blasts c) 10-20% blasts d) 20-30% blasts. For example, a participant with <5% blasts pretreatment with an on study blast increase of 50% which is now >5% showed bone marrow progression.
Participants Showing Cytogenetic Response by the International MDS Working Group (IWG 2000) During Double-blind Period as Evaluated by Central Review [ Time Frame: up to 52 weeks ] [ Designated as safety issue: No ]
The IWG criteria for evaluating cytogenetic response require a minimum of 20 baseline and post-baseline analyzable metaphases using conventional cytogenetic techniques. A major cytogenetic response is defined as no detectable cytogenetic abnormality if preexisting abnormality was present whereas a minor response requires ≥50% reduction in abnormal metaphases. Progression could be concluded based on as few as 3 metaphases if there were additional abnormalities. The best response is represented.
Participants Who Progressed to Acute Myeloid Leukemia (AML) During the Study [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
Number of participants who progressed to acute myeloid leukemia during the study, summarized at three different timepoints: first 16 weeks of the double-blind study, week 52 of the double-blind study, and up to 36 months which includes the double-blind and open-label periods of the study. The counts are cumulative by timeframe.
Kaplan Meier Estimates of Overall Survival by Randomized Group [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
Kaplan Meier estimate for median length of survival for study participants as they were randomized at the start of the study.
Participant Count of Deaths During Double-blind and Open-label by Randomized Group [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
Count of participant deaths throughout the entire study and reported by the original treatment assignment.
Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Endpoints at Week 12 [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
The Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire (Yellen, 1997) was used to assess health-related quality of life (HRQoL).

In addition to general HRQoL, the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning. The overall score range for the FACT-An is 0-188. Higher scores indicate better HRQoL.
Change From Baseline in the Trial Outcome Index-Anemia (TOI-An) Endpoints at Week 12 [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
The Trial Outcome Index-Anemia (TOI-An) composed of the physical and functional subscales of the FACT-G along with the Anemia subscale was used to assess health-related quality of life (HRQoL). The overall score range for the TOI-An is 0-136. Higher scores indicate better HRQoL.
Change From Baseline in the Trial Outcome Index-Fatigue (TOI-F) Endpoints at Week 12 [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
The Trial Outcome Index-Fatigue(TOI-F) composed of the physical and functional subscales of the FACT-G along with the fatigue items from the Anemia subscale was used to assess health-related quality of life (HRQoL). The overall score range for the TOI-F is 0-108. Higher scores indicate better HRQoL.
Summary of Participants Who Had Adverse Events (AE) During the Double-blind Period [ Time Frame: up to week 52 ] [ Designated as safety issue: Yes ]
Counts of study participants who had adverse events (AEs) during the double-blind period by MedDRA System Organ Class (SOC) and preferred term. 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 Terminology Criteria for AEs (CTCAE) was used to grade AE severity. Severity grade 3= severe and undesirable AE. Severity grade 4= life-threatening or disabling AE.

Enrollment:	205
Study Start Date:	July 2005
Study Completion Date:	June 2010
Primary Completion Date:	June 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo Comparator: Placebo Placebo matching to active study arms.	Drug: Placebo Placebo, matching to active study drug arms
Experimental: Lenalidomide 5 mg Lenalidomide 5 mg daily 28/28 days	Drug: Lenalidomide 5 mg Lenalidomide 5 mg daily 28/28 days Other Name: Revlimid
Experimental: Lenalidomide 10 mg Lenalidomide 10 mg daily 21/28 days	Drug: Lenalidomide 10 mg Lenalidomide 10 mg daily 21/28 days Other Name: Revlimid

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Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Must understand and voluntarily sign an informed consent form
Age 18 years at the time of signing the informed consent form
Documented diagnosis of myelodysplastic syndromes (MDS) that meets International Prognostic Scoring System (IPSS) criteria for low to intermediate-1-risk disease and has an associated del 5q(31) cytogenetic abnormality
Red blood cell (RBC) transfusion dependent anaemia defined as not having any 56 days without a RBC transfusion within at least the immediate 112 days
Must be able to adhere to the study visit schedule and other protocol requirements
Women of childbearing potential must have a negative pregnancy test prior to inclusion

Exclusion Criteria:

Pregnant or lactating females
Prior therapy with lenalidomide
Proliferative (white blood cell (WBC)= 12,000/mL) chronic myelomonocytic leukemia (CMML)
Prior >= grade-2 (using the National Cancer Institute (NCI)'s Common Terminology Criteria for AEs (CTCAE) (v 3.0)) allergic reaction to thalidomide
Prior desquamating (blistering) rash while taking thalidomide
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 >3 years
Use of cytotoxic chemotherapeutic agents or experimental agents (agents that are not commercially available) for the treatment of MDS within 28 days
Less than 6 months since prior allogeneic bone marrow transplantation
Less than 3 months since prior autologous bone marrow or stem cell transplantation
Less than 28 days since prior myelosuppressive anticancer biologic therapy
Recombinant human erythropoietin (rHuEPO) therapy received within 28 days
Known human immunodeficiency virus (HIV-1) positivity
Any serious medical condition or psychiatric illness that will prevent the subject from signing the informed consent form or will place the subject at unacceptable risk if he or she participates in the study

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00179621

Show 38 Study Locations

Sponsors and Collaborators

Celgene Corporation

ICON Clinical Research

Investigators

Study Director:

Jay Backstrom, MD

Celgene Corporation

More Information

Publications:

Fenaux, P., Giagounidis, A., Selleslag, D., Knight, R., Fu, T., Hellström-Lindberg, E. Effect of baseline EPO and prior erythropoiesis stimulating agents on RBC transfusion independence in Low-/Int-1-Risk MDS with del 5q treated with lenalidomide: A randomized phase 3 study (MDS-004). Haematologica 2010; 95[suppl.2]:125, abs. 0311.

Brandenburg, N., Fu, T., Revicki, D., Knight, R., Muus, P., Fenaux, P. Impact of lenalidomide on health-related quality of life in patients with RBC transfusion-dependent low- or int-1-risk myelodysplastic syndromes with del 5q: a randomized Phase 3 study (MDS-004). Haematologica 2010; 95[suppl.2]:127, abs. 0316

Brandenburg, N., Yu, R., Revicki, D. Reliability and Validity of the FACT-AN In Patients with Low or Int-1-Risk Myelodysplastic Syndromes with Deletion 5q. Blood ASH Annual Meeting Abstracts 2010 116:21 abs. 3827.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, Muus P, Te Boekhorst P, Sanz G, Del Cañizo C, Guerci-Bresler A, Nilsson L, Platzbecker U, Lübbert M, Quesnel B, Cazzola M, Ganser A, Bowen D, Schlegelberger B, Aul C, Knight R, Francis J, Fu T, Hellström-Lindberg E; MDS-004 Lenalidomide del5q Study Group. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood. 2011 Oct 6;118(14):3765-76. Epub 2011 Jul 13.

Göhring G, Giagounidis A, Büsche G, Hofmann W, Kreipe HH, Fenaux P, Hellström-Lindberg E, Schlegelberger B. Cytogenetic follow-up by karyotyping and fluorescence in situ hybridization: implications for monitoring patients with myelodysplastic syndrome and deletion 5q treated with lenalidomide. Haematologica. 2011 Feb;96(2):319-22. Epub 2010 Nov 25.

Responsible Party:	Jay Backstrom, MD, Vice President, Clinical Development MDS, Celgene Corporation
ClinicalTrials.gov Identifier:	NCT00179621 History of Changes
Other Study ID Numbers:	CC-5013-MDS-004, 2005-000454-73
Study First Received:	September 10, 2005
Results First Received:	February 9, 2011
Last Updated:	April 12, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by Celgene Corporation:

MDS
transfusion dependent
anaemia
cytogenetic abnormality 5q-
erythroid response

leukaemia
CC-5013
Celgene
revlimid
lenalidomide

Additional relevant MeSH terms:

Congenital Abnormalities
Chromosome Aberrations
Chromosome Disorders
Myelodysplastic Syndromes
Preleukemia
Pathologic Processes
Genetic Diseases, Inborn
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Lenalidomide
Thalidomide

Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Leprostatic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on May 21, 2013