Lenalidomide Versus Placebo in Myelodysplastic Syndromes With a Deletion 5q[31] Abnormality

Myelodysplastic Syndromes Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00179621
• Other study ID #: CC-5013-MDS-004
• Secondary ID: 2005-000454-73
• Status: Completed
• Phase: Phase 3
• First received: September 10, 2005
• Last updated: April 12, 2011
• Start date: July 2005
• Est. completion date: June 2010

Study information

• Verified date: April 2011
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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).

Description:

MDS-004 was a multicenter, randomized, double-blind, placebo-controlled, 3-arm study of 2 doses of lenalidomide versus placebo administered to RBC transfusion-dependent adults with low- or intermediate-1 risk MDS associated with a del 5q[31] cytogentetic abnormality. Potential participants that had a del 5q[31] cytogenetic abnormality plus other additional cytogenetic abnormalities were also eligible for enrollment. Transfusion-dependent anemia was defined as documentation that a participant with anemia due to MDS did not have any consecutive 56 days (8 weeks) that were RBC transfusion free during at least the 112 days (16 weeks) prior to Day 1 of the Pre-Randomization Phase.

This study was conducted in three phases:

1. a Pre-Randomization Phase

2. a Double-Blind Treatment Phase

3. an Open-Label Extension Phase

Potentially protocol-eligible participants entered the Pre-Randomization Phase and were evaluated for the inclusion and exclusion criteria for the Double-Blind Treatment Phase. The Pre-Randomization Phase was not to last for more than 56 days (8 weeks). When the participant's baseline RBC transfusion requirement was calculated, and it had been determined that all eligibility criteria had been met, the participant could be randomized for treatment in the Double-Blind Treatment Phase at the time of their next RBC transfusion. This RBC transfusion had to occur within 56 days of the participant's last previous RBC transfusion.

Participants meeting eligibility criteria were randomized (1:1:1 ratio) to receive either lenalidomide 10 mg/day on days 1-21, lenalidomide 5 mg/day on days 1-28, or placebo on days 1-28; all on a 28-day cycle. Randomization was performed using a validated interactive voice response system. Participants were stratified according to karyotype (IPSS karyotype score: 0 vs > 0; i.e., isolated del 5q[31] vs del 5q[31] plus ≥ 1 additional cytogenetic abnormality). A complete blood count (CBC), serum or plasma ferritin, and EPO levels were measured to determine baseline levels.

Participants who achieved at least a minor erythroid response (i.e. 50% decrease in transfusion requirements) by week 16 could continue treatment in the Double-Blind phase for up to 52 weeks, unless there was evidence of erythroid relapse, disease progression, or unacceptable toxicity. Those who did not achieve at least a minor erythroid response by week 16 were discontinued from the Double-Blind phase for lack of therapeutic efficacy, and unblinded and were potentially eligible for Open-Label treatment. All participants who completed the double-blind treatment phase (the first 52 weeks of the trial) without disease progression or erythroid relapse were unblinded and entered the Open-Label extension phase at their current lenalidomide dose. Participants in the placebo or lenalidomide 5 mg arms who failed to achieve at least a minor erythroid response by week 16 or who had an erythroid relapse could cross over to lenalidomide 5 mg or 10 mg, respectively, in the Open-Label Extension phase.

Lenalidomide treatment could be continued in the Open-label Extension phase for up to 3 years (156 weeks) of total study participation. Participants with disease progression at any time and participants in the lenalidomide 10 mg group who did not achieve at least a minor erythroid response by week 16 were withdrawn from the study and were ineligible for Open-Label treatment.

Serial measurements for efficacy and safety were performed every 28 days. In addition, CBCs were monitored weekly for the first 8 weeks, every 2 weeks for the next 8 weeks, and every 4 weeks thereafter. Bone marrow aspirate (BMA) and standard cytogenetic studies were performed at baseline, weeks 12, week 24, and every 24 weeks thereafter and when clinically indicated for assessment of disease progression. BMAs were submitted for central pathology review and sent to a central cytogenetics laboratory for processing and review. All participants were followed for overall survival (OS) and progression to acute myeloid leukemia (AML).

Lenalidomide or placebo dosing was reduced for dose-limiting toxicities according to the following dose reduction schedule:

• Lenalidomide 5 mg (starting dose)

• dose level −1 (5 mg every other day)

• dose level −2 (5 mg twice a week)

• dose level −3 (5 mg weekly)

• Lenalidomide 10 mg (starting dose)

• dose level −1 (5 mg daily)

• dose level −2 (5 mg every other day)

• dose level −3 (5 mg twice a week)

Participants who could not tolerate dose level −3 discontinued treatment. For grade 4 neutropenia, lenalidomide was required per protocol to be interrupted and resumed at a decreased dose level when the absolute neutrophil count (ANC) recovered to ≥ 500/μL. For grade 4 thrombocytopenia, lenalidomide was interrupted and then resumed at a decreased dose level when the platelet count recovered to: between ≥ 25,000/μL and < 50,000/μL on at least 2 occasions for ≥ 7 days; or ≥ 50,000 at any time, respectively. Prophylactic and therapeutic use of granulocyte colony-stimulating factors (G-CSF) or granulocyte macrophage colony-stimulating factors (GM-CSF) was allowed.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 205
• Est. completion date: June 2010
• Est. primary completion date: June 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chromosome Aberrations
• Chromosome Disorders
• Congenital Abnormalities
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Lenalidomide 5 mg
Lenalidomide 5 mg daily 28/28 days
• Lenalidomide 10 mg
Lenalidomide 10 mg daily 21/28 days
• Placebo
Placebo, matching to active study drug arms

Locations

Country	Name	City	State
Belgium	AZ St-Jan Brugge AV	Brugge
Belgium	UZ Gent	Gent
Belgium	UZ Gasthuisberg	Leuven
Belgium	CHU Mont Godine	Yvoir
France	CHU d'Angers Service des Maladies du Sang	Angers
France	Hopital Avicenne	Bobigny Cedex
France	CHRU Lille Service des Maladies du Sang	Lille
France	Institut Paoli-Calmettes	Marseille	Cedex 9
France	CHU Nantes Hematologie et Medicine interne	Nantes
France	CHU Archet 1Hematologie Clinique	Nice
France	Hôpital Cochin Hematologie Clinique	Paris
France	Centre Jean Bernhard Service Onco-Hematologie	Poitiers
France	Centre Henri Becquerel Service d'Hematologie Clinique	Rouen
France	CHU Purpan, Place du Dr Baylac, Pavillon des Médecines	Toulouse
France	CHU Purpan, Place du Dr. Baylac, Pavillion des Medecines	Toulouse
France	CHU Nancy Hematologie et Medecine interne	Vandoeuvre
Germany	Universitaetsklinikum Carl Gustav Carus	Dresden
Germany	St Johannes Hospital	Duisburg
Germany	Universitaetsklinikum Freiburg	Freiburg
Germany	Hannover Medical School	Hannover
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
Italy	Ospedale Niguarda Ca Granda	Milano
Italy	University of Pavia Division of Hematology	Pavia
Netherlands	University of Medical Centre	Nijmegen
Netherlands	Hematologie Erasmus MC	Rotterdam
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Universitario La Fe	Valencia
Sweden	SU/Sahlgrenska Section of Hematology & Coagulation	Goteborg
Sweden	Department of Medicine University Hospital	Lund
Sweden	Korolinska Institutet Department of Hematology	Stockholm
United Kingdom	The Royal Bournemouth Hospital	Bournemouth
United Kingdom	University Hospital of Wales, Dept of Haematology	Cardiff	Wales
United Kingdom	Ninewells Hospital and Medical School	Dundee
United Kingdom	Leed General Infirmary	Leeds	West Yorkshire
United Kingdom	Kings College Hospital, Denmark Hill	London
United Kingdom	Central Manchester and Manchester Children's University Hospitals NHS Trust	Manchester
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	John Radcliffe Hospital and the Weatherall Institute of Molecular Medicine	Oxford

Sponsors (2)

Lead Sponsor	Collaborator
Celgene Corporation	ICON Clinical Research

Countries where clinical trial is conducted

Belgium,  France,  Germany,  Israel,  Italy,  Netherlands,  Spain,  Sweden,  United Kingdom, 

References & Publications (6)

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

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.

Fenaux, P., Giagounidis, A., Beyne-Rauzy, O., Mufti, G., Mittelman, M., Muus, P., te Boekhorst, P., Sanz, G., Cazzola, M., Backstrom, J., Fu, T., Hellström-Lindberg, E. Prognostic Factors of Long-Term Outcomes In Low- or Int-1-Risk MDS with del5q Treated

Fenaux, P., Giagounidis, A., Selleslag, D. L., Beyne-Rauzy, O., Mittelman, M., Muus, P., Knight, R. D., Fu, T., Hellstrom-Lindberg, E., The MDS-004 Len del(5q) Study Group. Safety of lenalidomide (LEN) from a randomized phase III trial (MDS-004) in low-/i

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 rando

Fenaux, Pierre, Giagounidis, Aristotle, Selleslag, Dominik, Beyne-Rauzy, Odile, Mufti, Ghulam J, Mittelman, Moshe, Muus, Petra, te Boekhorst, Peter, Sanz, Guillermo, del Canizo, Consuelo, Guerci-Bresler, Agnes, Schlegelberger, Brigitte, Aul, Carlo, Kreipe

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for >= 26 Weeks (182 Days)	The count of study participants who had no RBC transfusions for 26 consecutive weeks or more during the double-blind period.	Up to 52 weeks	No
Secondary	Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for 56 Days	Count of study participants who had no RBC transfusions during any 56 or more consecutive study days during the double-blind period.	Up to 52 weeks	No
Secondary	Duration of Red Blood Cell (RBC) Transfusion Independence for Participants Who Became RBC Transfusion Independent for at Least 182 Days	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.	up to 3 years	No
Secondary	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	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.	Baseline, up to 52 weeks	No
Secondary	Participants' Response in Platelet Counts as Defined by the International MDS Working Group (IWG 2000) During Double-blind Period	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.	up to 52 weeks	No
Secondary	Participants' Response in Absolute Neutrophil Counts as Defined by the International MDS Working Group (IWG 2000) During Double-blind Period	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.	up to week 52	No
Secondary	Participants' Response Based on Bone Marrow Samples by the International MDS Working Group (IWG 2000) During Double-blind Period	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.	up to 52 weeks	No
Secondary	Participants Showing Cytogenetic Response by the International MDS Working Group (IWG 2000) During Double-blind Period as Evaluated by Central Review	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.	up to 52 weeks	No
Secondary	Participants Who Progressed to Acute Myeloid Leukemia (AML) During the Study	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.	up to 3 years	No
Secondary	Kaplan Meier Estimates of Overall Survival by Randomized Group	Kaplan Meier estimate for median length of survival for study participants as they were randomized at the start of the study.	up to 3 years	No
Secondary	Participant Count of Deaths During Double-blind and Open-label by Randomized Group	Count of participant deaths throughout the entire study and reported by the original treatment assignment.	up to 3 years	No
Secondary	Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Endpoints at Week 12	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.	Baseline, Week 12	No
Secondary	Change From Baseline in the Trial Outcome Index-Anemia (TOI-An) Endpoints at Week 12	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.	Baseline, Week 12	No
Secondary	Change From Baseline in the Trial Outcome Index-Fatigue (TOI-F) Endpoints at Week 12	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.	Baseline, Week 12	No
Secondary	Summary of Participants Who Had Adverse Events (AE) During the Double-blind Period	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.	up to week 52	Yes