Trial Outcomes & Findings for A Pharmacokinetic And Pharmacodynamic Study Of Oral Lenalidomide (Revlimid) In Subjects With Low- Or Intermediate-1-Risk Myelodysplastic Syndromes (NCT NCT00910858)

Last Updated: 2013-09-30

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

40 participants

Primary outcome timeframe

On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours post-dose.

Results posted on

2013-09-30

Participant Flow

A total of 40 participants were enrolled at 1 site in this study, with 12 participants enrolled in the Pharmacokinetic (PK) Phase of the study, 39 participants enrolled in the Monotherapy Phase of the study, and 23 participants enrolled in the Combined Treatment Phase of the study.

The Monotherapy Phase included an initial group of 24 patients (11 from the PK Phase and 13 newly enrolled) who participated in the multiple-dose PK assessment and a second group of 15 patients (15 mg Non-del 5q) for whom no PK samples were taken. Erythroid nonresponders or responders who relapsed could participate in the Combined Treatment Phase.

Participant milestones

Participant milestones
Measure	10 mg Non-del 5q 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.	15 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.	10 mg 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.
Pharmacokinetic Phase STARTED	9	0	3
Pharmacokinetic Phase COMPLETED	8	0	3
Pharmacokinetic Phase NOT COMPLETED	1	0	0
Monotherapy Phase STARTED	17	15	7
Monotherapy Phase Safety Population	17	15	7
Monotherapy Phase Pharmacokinetic Population	17	0	7
Monotherapy Phase COMPLETED	0	0	0
Monotherapy Phase NOT COMPLETED	17	15	7
Combined Treatment Phase STARTED	9	10	4
Combined Treatment Phase COMPLETED	0	0	0
Combined Treatment Phase NOT COMPLETED	9	10	4

Reasons for withdrawal

Reasons for withdrawal
Measure	10 mg Non-del 5q 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.	15 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.	10 mg 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.
Pharmacokinetic Phase Adverse Event	1	0	0
Monotherapy Phase Adverse Event	3	2	0
Monotherapy Phase Lack of therapeutic effect	9	6	4
Monotherapy Phase Withdrawal by Subject	1	3	1
Monotherapy Phase Protocol Violation	1	0	0
Monotherapy Phase Other	3	4	2
Combined Treatment Phase Lack of therapeutic effect	8	6	3
Combined Treatment Phase Withdrawal by Subject	0	2	0
Combined Treatment Phase Protocol Violation	1	0	0
Combined Treatment Phase Other	0	2	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	10 mg Non-del 5q n=17 Participants 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.	15 mg Non-del 5q n=15 Participants 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.	10 mg Del 5q n=7 Participants 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.	Total n=39 Participants Total of all reporting groups
Age Continuous	67.8 years STANDARD_DEVIATION 10.96 • n=5 Participants	73.4 years STANDARD_DEVIATION 6.51 • n=7 Participants	72.6 years STANDARD_DEVIATION 7.39 • n=5 Participants	70.8 years STANDARD_DEVIATION 9.07 • n=4 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	4 Participants n=7 Participants	4 Participants n=5 Participants	11 Participants n=4 Participants
Sex: Female, Male Male	14 Participants n=5 Participants	11 Participants n=7 Participants	3 Participants n=5 Participants	28 Participants n=4 Participants
Race/Ethnicity, Customized White	17 participants n=5 Participants	13 participants n=7 Participants	7 participants n=5 Participants	37 participants n=4 Participants
Race/Ethnicity, Customized Hispanic	1 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	2 participants n=4 Participants
Race/Ethnicity, Customized Other	1 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	2 participants n=4 Participants
Duration of MDS	2.8 years STANDARD_DEVIATION 2.28 • n=5 Participants	2.6 years STANDARD_DEVIATION 2.22 • n=7 Participants	4.2 years STANDARD_DEVIATION 4.74 • n=5 Participants	3.0 years STANDARD_DEVIATION 2.81 • n=4 Participants
International Prognostic Scoring System (IPSS) Score Low risk (0)	8 participants n=5 Participants	8 participants n=7 Participants	2 participants n=5 Participants	18 participants n=4 Participants
International Prognostic Scoring System (IPSS) Score Intermediate-1 (0.5-1.0)	9 participants n=5 Participants	7 participants n=7 Participants	5 participants n=5 Participants	21 participants n=4 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 0	2 participants n=5 Participants	4 participants n=7 Participants	1 participants n=5 Participants	7 participants n=4 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 1	14 participants n=5 Participants	11 participants n=7 Participants	6 participants n=5 Participants	31 participants n=4 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 2	1 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants
French-American-British (FAB) classification of MDS Refractory anemia (RA)	6 participants n=5 Participants	7 participants n=7 Participants	2 participants n=5 Participants	15 participants n=4 Participants
French-American-British (FAB) classification of MDS Refractory anemia with ringed sideroblasts (RARS)	5 participants n=5 Participants	6 participants n=7 Participants	0 participants n=5 Participants	11 participants n=4 Participants
French-American-British (FAB) classification of MDS Refractory anemia with excess blasts (RAEB)	3 participants n=5 Participants	1 participants n=7 Participants	4 participants n=5 Participants	8 participants n=4 Participants
French-American-British (FAB) classification of MDS Refractory anemia with excess blasts -1 (RAEB-1)	0 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants
French-American-British (FAB) classification of MDS Other	3 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	4 participants n=4 Participants
Serum erythropoietin level < 500 mIU/mL	9 participants n=5 Participants	4 participants n=7 Participants	2 participants n=5 Participants	15 participants n=4 Participants
Serum erythropoietin level ≥ 500 mIU/mL	7 participants n=5 Participants	2 participants n=7 Participants	5 participants n=5 Participants	14 participants n=4 Participants
Serum erythropoietin level Missing	1 participants n=5 Participants	9 participants n=7 Participants	0 participants n=5 Participants	10 participants n=4 Participants

PRIMARY outcome

Timeframe: On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours post-dose.

Population: All Pharmacokinetic Phase participants.

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.

Outcome measures

Outcome measures
Measure	10 mg Lenalidomide n=12 Participants Participants received a single oral dose of 10 mg lenalidomide on Day -7.	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.	10 mg 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.
PK Phase: Area-under-the Concentration-time Curve (AUC0-24) for Lenalidomide	817 ng*h/mL Geometric Coefficient of Variation 30.5	—	—

PRIMARY outcome

Timeframe: On Day 14 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, and 5 hours postdose.

Population: Monotherapy Phase pharmacokinetic population

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.

Outcome measures

Outcome measures
Measure	10 mg Lenalidomide n=24 Participants Participants received a single oral dose of 10 mg lenalidomide on Day -7.	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.	10 mg 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.
Monotherapy Phase: Area-under-the Concentration-time Curve (AUC0-5) for Lenalidomide Total Lenalidomide	563 ng*h/mL Geometric Coefficient of Variation 32.5	—	—
Monotherapy Phase: Area-under-the Concentration-time Curve (AUC0-5) for Lenalidomide S-Lenalidomide	315 ng*h/mL Geometric Coefficient of Variation 34.2	—	—
Monotherapy Phase: Area-under-the Concentration-time Curve (AUC0-5) for Lenalidomide R-Lenalidomide	248 ng*h/mL Geometric Coefficient of Variation 30.6	—	—

SECONDARY outcome

Timeframe: On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose.

Population: All Pharmacokinetic Phase participants

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

Outcome measures

Outcome measures
Measure	10 mg Lenalidomide n=12 Participants Participants received a single oral dose of 10 mg lenalidomide on Day -7.	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.	10 mg 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.
PK Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) Total Lenalidomide	179 ng/mL Geometric Coefficient of Variation 33.6	—	—
PK Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) S-Lenalidomide	101 ng/mL Geometric Coefficient of Variation 34.9	—	—
PK Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) R-Lenalidomide	78.3 ng/mL Geometric Coefficient of Variation 32.7	—	—

SECONDARY outcome

Timeframe: On Day 14 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, and 5 hours postdose.

Population: Monotherapy Phase pharmacokinetic population.

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

Outcome measures

Outcome measures
Measure	10 mg Lenalidomide n=24 Participants Participants received a single oral dose of 10 mg lenalidomide on Day -7.	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.	10 mg 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.
Monotherapy Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) Total Lenalidomide	185 ng/mL Geometric Coefficient of Variation 38.7	—	—
Monotherapy Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) S-Lenalidomide	104 ng/mL Geometric Coefficient of Variation 39	—	—
Monotherapy Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) R-Lenalidomide	80.7 ng/mL Geometric Coefficient of Variation 38.8	—	—

SECONDARY outcome

Timeframe: On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose.

Population: Pharmacokinetic Phase participants.

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).

Outcome measures

Outcome measures
Measure	10 mg Lenalidomide n=12 Participants Participants received a single oral dose of 10 mg lenalidomide on Day -7.	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.	10 mg 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.
PK Phase: Terminal Half-life (t1/2) Total Lenalidomide	3.72 hours Geometric Coefficient of Variation 19.5	—	—
PK Phase: Terminal Half-life (t1/2) S-Lenalidomide	4.14 hours Geometric Coefficient of Variation 29.0	—	—
PK Phase: Terminal Half-life (t1/2) R-Lenalidomide	3.58 hours Geometric Coefficient of Variation 21.4	—	—

SECONDARY outcome

Timeframe: On Day -7 at predose and over the intervals of 0-5, 5-8, 8-12, and 12-24 hours postdose.

Population: PK Phase participants for whom data was available.

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.

Outcome measures

Outcome measures
Measure	10 mg Lenalidomide n=8 Participants Participants received a single oral dose of 10 mg lenalidomide on Day -7.	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.	10 mg 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.
PK Phase: Percent of Administered Lenalidomide Excreted Over 24 Hours After a Single, Oral Dose Total Lenalidomide	65.1 percent of administered dose Geometric Coefficient of Variation 13.5	—	—
PK Phase: Percent of Administered Lenalidomide Excreted Over 24 Hours After a Single, Oral Dose S-Lenalidomide	67.9 percent of administered dose Geometric Coefficient of Variation 13.9	—	—
PK Phase: Percent of Administered Lenalidomide Excreted Over 24 Hours After a Single, Oral Dose R-Lenalidomide	62.2 percent of administered dose Geometric Coefficient of Variation 14.0	—	—

SECONDARY outcome

Timeframe: On Day 14, at predose and over the interval of 0-5 hours postdose.

Population: Monotherapy Phase Pharmacokinetic Population.

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.

Outcome measures

Outcome measures
Measure	10 mg Lenalidomide n=24 Participants Participants received a single oral dose of 10 mg lenalidomide on Day -7.	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.	10 mg 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.
Monotherapy Phase: Percent of Lenalidomide Excreted Over 5 Hours Post Day 14 Dose Total Lenalidomide	34.0 percent of administered dose Geometric Coefficient of Variation 60.3	—	—
Monotherapy Phase: Percent of Lenalidomide Excreted Over 5 Hours Post Day 14 Dose S-Lenalidomide	35.4 percent of administered dose Geometric Coefficient of Variation 59.0	—	—
Monotherapy Phase: Percent of Lenalidomide Excreted Over 5 Hours Post Day 14 Dose R-Lenalidomide	32.5 percent of administered dose Geometric Coefficient of Variation 62.0	—	—

SECONDARY outcome

Timeframe: From the date of first dose until 30 days after the last dose (up to 1218 days)

Population: 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 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.

Outcome measures

Outcome measures
Measure	10 mg Lenalidomide n=32 Participants Participants received a single oral dose of 10 mg lenalidomide on Day -7.	Del 5q n=7 Participants 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.	10 mg 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.
Time to Grade 4 Neutropenia or Thrombocytopenia Grade 4 Neutropenia	69.0 days Interval 11.0 to 168.0	28.0 days Interval 17.0 to 36.0	—
Time to Grade 4 Neutropenia or Thrombocytopenia Grade 4 Thrombocytopenia	53.0 days Interval 22.0 to 141.0	29.0 days Interval 22.0 to 36.0	—

SECONDARY outcome

Timeframe: Assessed every 28 days until study discontinuation (up to 1218 days).

Population: 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.

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).

Outcome measures

Outcome measures
Measure	10 mg Lenalidomide n=17 Participants Participants received a single oral dose of 10 mg lenalidomide on Day -7.	Del 5q n=15 Participants 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.	10 mg Del 5q n=7 Participants 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.
Percentage of Participants With a Erythroid Response Across All Phases Major response	17.6 percentage of participants	40.0 percentage of participants	85.7 percentage of participants
Percentage of Participants With a Erythroid Response Across All Phases Minor response	5.9 percentage of participants	0 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: Assessed every 28 days until study discontinuation (up to 1218 days)

Population: Safety population.

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.

Outcome measures

Outcome measures
Measure	10 mg Lenalidomide n=16 Participants Participants received a single oral dose of 10 mg lenalidomide on Day -7.	Del 5q n=23 Participants 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.	10 mg Del 5q n=39 Participants 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.
Percentage of Participants Overall With Erythroid Response by Baseline Erythropoietin Level Baseline EPO ≤ 500 mIU/mL	62.5 percentage of participants	47.8 percentage of participants	53.8 percentage of participants
Percentage of Participants Overall With Erythroid Response by Baseline Erythropoietin Level Baseline EPO > 500 mIU/mL	37.5 percentage of participants	39.1 percentage of participants	38.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Week 16

Population: Unable to obtain sufficient bone marrow samples to perform analyses.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Pre-Study and Week 16

Population: Unable to obtain sufficient bone marrow samples to perform analyses

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

Outcome measures

Outcome data not reported

Adverse Events

10 mg Lenalidomide

Serious events: 10 serious events

Other events: 24 other events

Deaths: 0 deaths

15 mg Lenalidomide

Serious events: 5 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Associate Director, Clinical Trials Disclosure

Celgene Corporation

Phone: 1-888-260-1599

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee * Multicenter publication must include input from investigators and Celgene, agreement to be established before publication. It has priority over subset (single center) publication, for duration of 1 year after study completion. * Individual investigators have publication right after multicenter publication is complete (or 1 year after study completion), whichever is first. In this case, Celgene has the right to comment and right to ask delay of publication for 60 days.
Publication restrictions are in place

Restriction type: OTHER

Measure	10 mg Lenalidomide n=24 participants at risk 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.	15 mg Lenalidomide n=15 participants at risk 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.
General disorders Asthenia	0.00% 0/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	6.7% 1/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
General disorders Disease progression NOS	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	0.00% 0/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
General disorders Fatigue	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	0.00% 0/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Infections and infestations Pneumonia NOS	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	6.7% 1/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Infections and infestations Parotitis	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	0.00% 0/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Infections and infestations Sepsis NOS	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	0.00% 0/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Cardiac disorders Cardiac failure congestive	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	6.7% 1/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Cardiac disorders Myocardial infarction	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	0.00% 0/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Musculoskeletal and connective tissue disorders Costochondritis	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	0.00% 0/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Musculoskeletal and connective tissue disorders Pain in limb	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	0.00% 0/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Nervous system disorders Dizziness	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	0.00% 0/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Nervous system disorders Transient ischemic attack	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	0.00% 0/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnea NOS	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	0.00% 0/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Respiratory, thoracic and mediastinal disorders Epistaxis	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	0.00% 0/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Vascular disorders Deep vein thrombosis	0.00% 0/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	6.7% 1/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Vascular disorders Gangrene NOS	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	0.00% 0/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Gastrointestinal disorders Diarrhea NOS	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	0.00% 0/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Gastrointestinal disorders Nausea	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	0.00% 0/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Gastrointestinal disorders Vomiting NOS	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	0.00% 0/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Injury, poisoning and procedural complications Transfusion reaction	4.2% 1/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	0.00% 0/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.
Renal and urinary disorders Urinary retention	0.00% 0/24 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.	6.7% 1/15 • The safety analyses were conducted on data collected from the time of first dose of study drug to 30 days after the last dose of study drug.