Clinical trial NCT00179621: Lenalidomide Versus Placebo in Myelodysplastic Syndromes With a Deletion 5q[31] Abnormality
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Myelodysplastic Syndromes
Keywords: MDS
transfusion dependent
anaemia
cytogenetic abnormality 5q-
erythroid response
leukaemia
CC-5013
Celgene
revlimid
lenalidomide
Lead sponsor: Celgene
Sponsor class: INDUSTRY
Collaborators: name: ICON Clinical Research
First posted: 2005-09-16
Enrollment: 205
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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).

Detailed 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.

Eligibility 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

Primary outcomes:
measure: Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for >= 26 Weeks (182 Days)
timeFrame: Up to 52 weeks
Secondary outcomes:
measure: Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for 56 Days
timeFrame: Up to 52 weeks
measure: Duration of Red Blood Cell (RBC) Transfusion Independence for Participants Who Became RBC Transfusion Independent for at Least 182 Days
timeFrame: up to 3 years
measure: 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
timeFrame: Baseline, up to 52 weeks
measure: Participants' Response in Platelet Counts as Defined by the International MDS Working Group (IWG 2000) During Double-blind Period
timeFrame: up to 52 weeks
measure: Participants' Response in Absolute Neutrophil Counts as Defined by the International MDS Working Group (IWG 2000) During Double-blind Period
timeFrame: up to week 52
measure: Participants' Response Based on Bone Marrow Samples by the International MDS Working Group (IWG 2000) During Double-blind Period
timeFrame: up to 52 weeks
measure: Participants Showing Cytogenetic Response by the International MDS Working Group (IWG 2000) During Double-blind Period as Evaluated by Central Review
timeFrame: up to 52 weeks
measure: Participants Who Progressed to Acute Myeloid Leukemia (AML) During the Study
timeFrame: up to 3 years
measure: Kaplan Meier Estimates of Overall Survival by Randomized Group
timeFrame: up to 3 years
measure: Participant Count of Deaths During Double-blind and Open-label by Randomized Group
timeFrame: up to 3 years
measure: Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Endpoints at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in the Trial Outcome Index-Anemia (TOI-An) Endpoints at Week 12
timeFrame: Baseline, Week 12
measure: Change From Baseline in the Trial Outcome Index-Fatigue (TOI-F) Endpoints at Week 12
timeFrame: Baseline, Week 12
measure: Summary of Participants Who Had Adverse Events (AE) During the Double-blind Period
timeFrame: up to week 52
Other outcomes:
Locations:
city: Brugge
country: Belgium
facility: AZ St-Jan Brugge AV
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Gasthuisberg
city: Yvoir
country: Belgium
facility: CHU Mont Godine
city: Marseille
country: France
facility: Institut Paoli-Calmettes
state: Cedex 9
city: Angers
country: France
facility: CHU d'Angers Service des Maladies du Sang
city: Bobigny Cedex
country: France
facility: Hopital Avicenne
city: Lille
country: France
facility: CHRU Lille Service des Maladies du Sang
city: Nantes
country: France
facility: CHU Nantes Hematologie et Medicine interne
city: Nice
country: France
facility: CHU Archet 1Hematologie Clinique
city: Paris
country: France
facility: Hôpital Cochin Hematologie Clinique
city: Poitiers
country: France
facility: Centre Jean Bernhard Service Onco-Hematologie
city: Rouen
country: France
facility: Centre Henri Becquerel Service d'Hematologie Clinique
city: Toulouse
country: France
facility: CHU Purpan, Place du Dr Baylac, Pavillon des Médecines
city: Toulouse
country: France
facility: CHU Purpan, Place du Dr. Baylac, Pavillion des Medecines
city: Vandoeuvre
country: France
facility: CHU Nancy Hematologie et Medecine interne
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus
city: Duisburg
country: Germany
facility: St Johannes Hospital
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Hannover
country: Germany
facility: Hannover Medical School
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Milano
country: Italy
facility: Ospedale Niguarda Ca Granda
city: Pavia
country: Italy
facility: University of Pavia Division of Hematology
city: Nijmegen
country: Netherlands
facility: University of Medical Centre
city: Rotterdam
country: Netherlands
facility: Hematologie Erasmus MC
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
city: Goteborg
country: Sweden
facility: SU/Sahlgrenska Section of Hematology & Coagulation
city: Lund
country: Sweden
facility: Department of Medicine University Hospital
city: Stockholm
country: Sweden
facility: Korolinska Institutet Department of Hematology
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales, Dept of Haematology
state: Wales
city: Leeds
country: United Kingdom
facility: Leed General Infirmary
state: West Yorkshire
city: Bournemouth
country: United Kingdom
facility: The Royal Bournemouth Hospital
city: Dundee
country: United Kingdom
facility: Ninewells Hospital and Medical School
city: London
country: United Kingdom
facility: Kings College Hospital, Denmark Hill
city: Manchester
country: United Kingdom
facility: Central Manchester and Manchester Children's University Hospitals NHS Trust
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital and the Weatherall Institute of Molecular Medicine
Study officials:
affiliation: Celgene Corporation
name: Jay Backstrom, MD
role: STUDY_DIRECTOR
References:
citation: 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, Hans, Goehring, Gudrun, Knight, Robert, Francis, John, Fu, Tommy, Hellstrom-Lindberg, Eva. RBC Transfusion Independence and Safety Profile of Lenalidomide 5 or 10 mg in Pts with Low- or Int-1-Risk MDS with Del5q: Results From a Randomized Phase III Trial (MDS-004). ASH Annual Meeting Abstracts 2009 114: 944.
citation: 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-/int-1-risk myelodysplastic syndromes (MDS) with a del(5q) abnormality. J Clin Oncol (Meeting Abstracts) 2010 28: 6598
citation: 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.
citation: 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
citation: 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 with Lenalidomide (LEN): Results From a Randomized Phase 3 Trial (MDS-004). Blood ASH Annual Meeting Abstracts 2010 116:21 abs. 4027.
citation: 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.
citation: 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.
citation: Saft L, Karimi M, Ghaderi M, Matolcsy A, Mufti GJ, Kulasekararaj A, Gohring G, Giagounidis A, Selleslag D, Muus P, Sanz G, Mittelman M, Bowen D, Porwit A, Fu T, Backstrom J, Fenaux P, MacBeth KJ, Hellstrom-Lindberg E. p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q). Haematologica. 2014 Jun;99(6):1041-9. doi: 10.3324/haematol.2013.098103. Epub 2014 Mar 28.
citation: Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, Muus P, Te Boekhorst P, Sanz G, Del Canizo C, Guerci-Bresler A, Nilsson L, Platzbecker U, Lubbert M, Quesnel B, Cazzola M, Ganser A, Bowen D, Schlegelberger B, Aul C, Knight R, Francis J, Fu T, Hellstrom-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. doi: 10.1182/blood-2011-01-330126. Epub 2011 Jul 13.
citation: Gohring G, Giagounidis A, Busche G, Hofmann W, Kreipe HH, Fenaux P, Hellstrom-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. doi: 10.3324/haematol.2010.026658. Epub 2010 Nov 25.