Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Syndrome

Preleukemia

Myelodysplastic Syndromes

Bone Marrow Diseases

Hematologic Diseases

Precancerous Conditions

Antineoplastic Agents

All Drugs and Chemicals

Hematinics

Lenalidomide

Epoetin Alfa

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

Participants in the Pharmacokinetic Phase received a single 10 mg oral dose of lenalidomide on Day -7. During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure.

During the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.

Following the enrollment of the first 25 patients into the Monotherapy Phase, a second group of 15 patients with low- or intermediate-1-risk MDS not associated with a del 5q (non-del 5q) cytogenetic abnormality were enrolled to receive 15 mg of lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. During the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 15 mg lenalidomide in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.

Lenalidomide 5-mg capsules for oral administration

Recombinant human erythropoietin (rhu-EPO) subcutaneous injection of 40,000 units.

Recombinant human erythropoietin

Robert Knight, MD

The purpose of this study is to assess pharmacokinetic and pharmacodynamic characteristics of oral lenalidomide monotherapy administered to patients with Low- or Intermediate-1-risk Myelodysplastic Syndrome (MDS).

A Pharmacokinetic And Pharmacodynamic Study Of Oral Lenalidomide (Revlimid) In Subjects With Low- Or Intermediate-1-Risk Myelodysplastic Syndromes

Area under the plasma concentration-time curve from Time 0 to 24 hours post-dose for lenalidomide after a single dose, calculated using the log-linear trapezoidal method.

Area under the plasma concentration-time curve from Time 0 to 5 hours postdose for lenalidomide (its R- and S- enantiomers and the enantiomers combined) after multiple dosing for 14 days, calculated using the log-linear trapezoidal method.

The maximum observed plasma concentration (Cmax) of lenalidomide (its R- and S- enantiomers and the enantiomers combined) after a single dose on day -7.

The Maximum observed plasma concentration (Cmax) of lenalidomide (its R- and S- enantiomers and the enantiomers combined) after multiple dosing for 14 days.

The apparent terminal half-life is the time required for plasma concentration to decrease by 50% after pseudo-equilibrium of distribution has been reached, and calculated as the natural logarithm of 2 (0.693) / Apparent terminal rate constant (λz).

Percent of the administered dose of lenalidomide excreted unchanged in urine over 24 hours postdose after a single dose on Day -7, calculated as:

(amount excreted unchanged in urine over 24 hours postdose / Dose) \* 100.

The dose was 10 mg for total lenalidomide and 5 mg for the enantiomers.

Percent of the administered lenalidomide dose excreted unchanged in urine over 5 hours postdose after multiple dosing for 14 days, calculated as:

(amount excreted unchanged in urine over the first 5 hours postdose / Dose) \* 100.

The dose was 10 mg for total lenalidomide and 5 mg for the enantiomers.

Time to the first event of grade 4 neutropenia or thrombocytopenia, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0, was calculated as date of first event - date of first dose + 1.

Erythroid response was categorized as either a major response or a minor response. A major response was defined as red blood cell (RBC) transfusion independence during any consecutive 56-day period and an increase in hemoglobin of at least 1.5 g/dL. A minor response was defined as a ≥ 50% or ≥ 4 unit decrease in RBC transfusions from pretreatment requirements (the number of RBC transfusions required over an 8-week period before the start of study drug treatment).

To evaluate the predictive value of pretreatment serum erythropoietin (EPO) concentration for erythroid response to lenalidomide, the percentage of erythroid responders versus non-responders were stratified by Baseline EPO levels (≤ 500 mIU/mL versus \> 500 mIU/mL). Response includes participants with either a major or minor response.

Bone marrow cellularity is the volume ratio of hematopoietic stem cells and adipocytes (fat cells). Due to the small number of bone marrow samples, this analysis was not performed.

Due to the low number of bone marrow samples collected this analysis was not performed.

Celgene Corporation

Participants with low- or intermediate-1-risk myelodysplastic syndromes (MDS) received a single 10 mg oral dose of lenalidomide on Day -7 in the Pharmacokinetic Phase.

During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure.

After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.

10 mg Lenalidomide

Participants with low- or intermediate-1-risk MDS were enrolled directly into the Monotherapy Phase and received 15 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure.

After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 15 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.

15 mg Lenalidomide

Participants with low- or intermediate-1-risk myelodysplastic syndromes (MDS) not associated with a deletion 5q (del 5q) cytogenetic abnormality received a single 10 mg oral dose of lenalidomide on Day -7 in the Pharmacokinetic Phase.

During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure.

After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.

10 mg Non-del 5q

Participants with low- or intermediate-1-risk MDS not associated with a deletion 5q (del 5q) cytogenetic abnormality were enrolled directly into the Monotherapy Phase and received 15 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure.

After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 15 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.

15 mg Non-del 5q

Participants with a deletion 5q (del 5q) cytogenetic abnormality received a single 10 mg oral dose of lenalidomide on Day -7 in the Pharmacokinetic Phase.

During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure.

After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg of lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.

10 mg Del 5q

Total

Age Continuous

Sex: Female, Male

White

Hispanic

Other

Participants could select more than 1 race option.

Race/Ethnicity, Customized

Duration of MDS

Low risk (0)

Intermediate-1 (0.5-1.0)

The MDS IPSS score = sum of marrow blast + karyotype + cytopenia score. Score ranges from 0 (low risk) to 3.5 (high risk).

International Prognostic Scoring System (IPSS) Score

ECOG performance status: 0 = Fully active, no restrictions; 1 = Restricted but ambulatory and capable of light work; 2 = Ambulatory and capable of self-care but unable to work.

Eastern Cooperative Oncology Group (ECOG) Performance Status

Refractory anemia (RA)

Refractory anemia with ringed sideroblasts (RARS)

Refractory anemia with excess blasts (RAEB)

Refractory anemia with excess blasts -1 (RAEB-1)

Refractory anemia: characterized by less than 5% primitive blood cells (myeloblasts) in the bone marrow and pathological abnormalities primarily seen in red cell precursors; RARS: distinguished by the presence of 15% or greater red cell precursors in the marrow being abnormal iron-stuffed cells called "ringed sideroblasts"; RAEB: characterized by 5-20% myeloblasts in the marrow; RAEB-1: characterized by 5% to 9% blasts in the bone marrow and less than 5% blasts in the blood.

French-American-British (FAB) classification of MDS

< 500 mIU/mL

≥ 500 mIU/mL

Missing

Serum erythropoietin level

Associate Director, Clinical Trials Disclosure

Participants received a single oral dose of 10 mg lenalidomide on Day -7.

PK Phase: Area-under-the Concentration-time Curve (AUC0-24) for Lenalidomide

Total Lenalidomide

S-Lenalidomide

R-Lenalidomide

PK Phase: Maximum Plasma Concentration of Lenalidomide (Cmax)

During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily.

Monotherapy Phase pharmacokinetic population.

Monotherapy Phase: Maximum Plasma Concentration of Lenalidomide (Cmax)

PK Phase: Terminal Half-life (t1/2)

PK Phase participants for whom data was available.

PK Phase: Percent of Administered Lenalidomide Excreted Over 24 Hours After a Single, Oral Dose

Monotherapy Phase Pharmacokinetic Population.

Monotherapy Phase: Percent of Lenalidomide Excreted Over 5 Hours Post Day 14 Dose

Grade 4 Neutropenia

Grade 4 Thrombocytopenia

Participants with low- or intermediate-1-risk myelodysplastic syndromes (MDS) not associated with a deletion 5q (del 5q) cytogenetic abnormality received 10 or 15 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure.

During the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.

Non-del 5q

Participants with a deletion 5q (del 5q) cytogenetic abnormality received 10 mg oral lenalidomide once daily in the Monotherapy Phase. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure.

During the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg of lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.

Del 5q

Safety population, which comprised all enrolled patients who took at least 1 dose of study drug during the Monotherapy Phase or the Combined Treatment Phase.

Time to Grade 4 Neutropenia or Thrombocytopenia

Major response

Minor response

Percentage of Participants With a Erythroid Response Across All Phases

Baseline EPO ≤ 500 mIU/mL

Baseline EPO > 500 mIU/mL

Responders

Participants who were not erythroid responders.

Non-responders

All participants in the Safety population.

Overall

Percentage of Participants Overall With Erythroid Response by Baseline Erythropoietin Level

Participants with low- or intermediate-1-risk myelodysplastic syndromes (MDS) not associated with a deletion 5q (del 5q) cytogenetic abnormality received 10 or 15 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure.

After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.

Participants with a deletion 5q (del 5q) cytogenetic abnormality received 10 mg oral lenalidomide once daily in the Monotherapy Phase. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure.

After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg of lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment.

Unable to obtain sufficient bone marrow samples to perform analyses.

Change From Baseline in Bone Marrow Cellularity and Correlation With Grade 4 Myelosuppression

Monotherapy Phase pharmacokinetic population

Spots Global Cancer Trial Database for A Pharmacokinetic And Pharmacodynamic Study Of Oral Lenalidomide (Revlimid) In Subjects With Low- Or Intermediate-1-Risk Myelodysplastic Syndromes

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Study Description

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