Symptoms and General Pathology

All Conditions

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Rare Diseases

Syndrome

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Myelodysplastic Syndromes

Disease Progression

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Quality of Life

Anti-Inflammatory Agents

Antirheumatic Agents

Analgesics

All Drugs and Chemicals

Hematinics

Chrysarobin

Lenograstim

Mitogens

Darbepoetin alfa

Red cell transfusion support to achieve a predicted post-transfusion haemoglobin of 11.0 to 12.0 g/dl at a quantity and frequency such that the minimum haemoglobin is never below 8.0 g/dl

Aranesp 500 mcg vials once every 2 weeks.

Darbepoetin alpha

300 mcg vials twice a week, 3-4 days apart

Filgrastim

Red cell transfusion support to achieve a predicted post-transfusion haemoglobin of 11.0 to 12.0 g/dl at a quantity and frequency such that the minimum haemoglobin is never below 8.0 g/dl or such that the patient is never excessively symptomatic, according to local transfusion guidelines/policy.

Blood Red Cell Transfusion

Eva Controle, BSc

REGIME Coordinators

Data Manager

Sarah Knight

Samir G Agrawal

Aloysius Ho

Samir G Agrawal, MRCP FRCPath PhD

REGIME is comparing two treatments, with Darbepoetin Alpha (DA) and Filgrastim (Granulocyte Colony Stimulating Factor, G-CSF), to the standard treatment for Myelodysplastic Syndrome (MDS).

After giving Informed Consent patients will undergo a number of tests to confirm eligibility. Once eligibility is confirmed patients will be randomly assigned to one of the three treatments group: A: Darbepoetin Alpha (DA), B: Darbepoetin Alpha and Filgrastim (DA+G-CSF), C: Blood transfusion only. Patients will be required to attend the clinic once a month for 24 weeks. After 24 weeks if a patient has reacted favorably to the treatment they may continue on the treatment regime up to 52 weeks. After week 24 all patients will be required to attend the clinic twice more, at week 36 and 52.

Patients will be followed for a further 5 years to record loss of response, transformation to Acute Myeloid Leukaemia and/or Refractory Anemia with Excess Blasts and death.

Comparison Study of Standard Care Against Combination of Growth Factors Agents for Low-risk Myelodysplastic Syndromes

REGIME: A Randomised Controlled Trial of Prolonged Treatment With Darbepoetin Alpha, With or Without Recombinant Human Granulocyte Colony Stimulating Factor, Versus Best Supportive Care in Patients With Low-risk Myelodysplastic Syndromes (MDS).

To compare the Quality of Life of low risk Myelodysplastic Syndrome (MDS) patients randomised to receive prolonged treatment with DA alone, DA with G-CSF or best supportive care alone

To compare the haemoglobin response of low risk Myelodysplastic Syndrome (MDS) patients randomised to receive prolonged treatment with DA alone, DA with G-CSF or best supportive care alone

To assess the utility of prognostic factor and predictive factor assessment, in particular against the predictive model proposed by Hellstrom-Lindberg.

Cancer Research UK

Amgen

Barts & The London NHS Trust

Dr Samir G. Agrawal

Diseases and Abnormalities at or Before Birth

Leukemia

Congenital Abnormalities

Anemia

Chromosome Aberrations

Chromosome Disorders

Chromosome 5q Deletion

Antineoplastic Agents

Lenalidomide

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

Lenalidomide 5 mg

Lenalidomide 10 mg

Placebo, matching to active study drug arms

Placebo

Jay Backstrom, MD

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).

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.

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

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

The count of study participants who had no RBC transfusions for 26 consecutive weeks or more during the double-blind period.

Count of study participants who had no RBC transfusions during any 56 or more consecutive study days during the double-blind period.

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.

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.

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.

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.

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.

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.

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 estimate for median length of survival for study participants as they were randomized at the start of the study.

Count of participant deaths throughout the entire study and reported by the original treatment assignment.

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.

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.

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.

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.

ICON Clinical Research

Celgene Corporation

Jay Backstrom, MD, Vice President, Clinical Development MDS

Lenalidomide 10 mg daily for 21 of 28 days

Participants receiving placebo in the Double-Blind phase and Lenalidomide in the Open-Label phase.

Placebo Crossover to 5 mg Open-label Period

Total

Age Continuous

Sex: Female, Male

White

Other

Race/Ethnicity, Customized

Missing

5q- (31-33) Chromosomal Abnormality

Low risk (0)

Intermediate-1 (0.5 - 1.0)

Intermediate-2 (1.5 - 2.0)

High Risk (≥ 2.5)

Missing data

The international prognostic scoring system (IPSS) is a standard for risk assessment in primary myelodysplastic syndromes (MDS) that categorizes prognoses taking into account cytogenetics, cytopenias, blasts and blood counts. The IPSS prognostic subgroups consist of low-, intermediate-1-, intermediate-2-, and high-risk groups. The scale is 0-3.5 at 0.5 increments. Scores of 0=Low; 0.5-1.0=Int-1; 1.5-2.0=Int-2; 2.5-3.5=High risk which corresponds to poorer prognosis. The assessment was performed by the Central Reviewer.

International Prognostic Scoring System (IPSS)

Refractory anemia (RA)

Refractory anemia with ringed sideroblasts (RARS)

Refractory anemia with excess blasts (RAEB)

Chronic myelomonocytic leukemia (CMML)

RAEB in transformation

Chronic myelogenous leukemia (CML)

Specimen not adequate from diagnosis

Other or missing

FAB is a classification system for five (5) subtypes of myelodysplastic syndrome that are distinguished by the percentage of myeloblasts, presence or absence of ringed sideroblasts or a monocytosis. Classification was made by the Central Reviewer.

French-American-British (FAB) Classification

Associate Director, Clinical Trials Disclosure

The modified intent-to-treat (mITT) population included all participants with centrally-confirmed Low- or Int-1-risk MDS with del 5q\[31\] and documented RBC transfusion dependence who had received ≥ 1 dose of study drug.

Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for >= 26 Weeks (182 Days)

Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for 56 Days

The modified intent-to-treat (mITT) population included all participants who achieved RBC transfusion independence for at least 182 days.

Duration of Red Blood Cell (RBC) Transfusion Independence for Participants Who Became RBC Transfusion Independent for at Least 182 Days

The modified intent-to-treat (mITT) population included all participants with centrally-confirmed Low- or Int-1-risk MDS with del 5q\[31\] and documented RBC transfusion dependence who had received ≥ 1 dose of study drug. MITT participants who were transfusion independent for \>= 182 study days 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

Major

Minor

None

The modified intent-to-treat (mITT) population included all participants with centrally-confirmed Low- or Int-1-risk MDS with del 5q\[31\] and documented RBC transfusion dependence who had received ≥ 1 dose of study drug. Additionally, the participant must have had a baseline platelet count of \<100,000/mm\^3 to be included in the analysis.

Participants' Response in Platelet Counts as Defined by the International MDS Working Group (IWG 2000) During Double-blind Period

The modified intent-to-treat (mITT) population included all participants with centrally-confirmed Low- or Int-1-risk MDS with del 5q\[31\] and documented RBC transfusion dependence who had received ≥ 1 dose of study drug. Additionally, the participant must have had a baseline absolute neutrophil counts (ANC) \< 1,000/mm\^3.

Participants' Response in Absolute Neutrophil Counts as Defined by the International MDS Working Group (IWG 2000) During Double-blind Period

Complete remission

Partial remission

Stable Disease

Progression

Intent to treat population. Participants represented in the treatment groups to which they were randomized. Placebo response is limited to the double-blind phase. There were 10 responders in the placebo group who achieved their response under lenalidomide treatment after crossover to open-label.

Participants' Response Based on Bone Marrow Samples by the International MDS Working Group (IWG 2000) During Double-blind Period

Major response

Minor response

Cytogenetic progression

Not evaluable/data not available

Modified intent to treat population, which is defined as participants with centrally-confirmed Low- or Int-1-risk MDS with del 5q\[31\] and documented RBC transfusion dependence who had received ≥ 1 dose of study drug. Participants had to have had more than 1 post-baseline assessment in order to be evaluable for cytogenetic response.

Participants Showing Cytogenetic Response by the International MDS Working Group (IWG 2000) During Double-blind Period as Evaluated by Central Review

Double-Blind (first 16 weeks)

Double-Blind (52 weeks)

Double-Blind + Open-Label

Intent to treat population. Participants represented in the treatment groups to which they were randomized.

Participants Who Progressed to Acute Myeloid Leukemia (AML) During the Study

Safety population: All randomized participants who received any Lenalidomide or placebo.

Kaplan Meier Estimates of Overall Survival by Randomized Group

Participant Count of Deaths During Double-blind and Open-label by Randomized Group

Participants who had both Baseline and Week 12 FACT-An data.

Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Endpoints at Week 12

Participants who had both Baseline and Week 12 TOI-An data.

Change From Baseline in the Trial Outcome Index-Anemia (TOI-An) Endpoints at Week 12

Participants who had both Baseline and Week 12 TOI-F data.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Comparison Study of Standard Care Against Combination of Growth Factors Agents for Low-risk Myelodysplastic Syndromes	NCT01196715	Myelodysplastic...	Darbepoetin alp... Filgrastim Blood Red Cell ...	18 Years -	Barts & The London NHS Trust
Lenalidomide Versus Placebo in Myelodysplastic Syndromes With a Deletion 5q[31] Abnormality	NCT00179621	Myelodysplastic...	Lenalidomide 5 ... Lenalidomide 10... Placebo	18 Years -	Celgene

Spots Global Cancer Trial Database for erythroid response